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A Patient with Lung Infection |
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Develop a differential diagnosis based on the case presentation
A 48-year-old male with no history of tobacco use was admitted for evaluation of a right upper lobe lung mass. Five months prior to admission, the patient developed a fever and persistent cough productive of white sputum with slight hemoptysis. He was treated with an oral antibiotic. Three months prior to admission, a chest radiograph revealed a masslike lesion in the right upper lung anteriorly, near the chest wall. He denied any chest pain, dyspnea on exertion, or history of tuberculosis. A purified protein derivative (PPD) skin test was nonreactive. A bronchoscopy performed two months prior to admission did not reveal any endobronchial lesion, and a cytologic exmination was negative for cancer. In the month of admission, a repeat chest radiograph revealed that the density in the right lung had increased in size since the previous radiograph:
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QUESTIONS
and
ANSWERS
1.
What chronic infections of fungal and bacterial organisms cause lung masses of the type found in this patient? What noninfectious processes could cause lung masses of this type?
ANSWER 1.
ANSWER 2.
3. The patient was eventually admitted to the hospital, where she underwent a right thoracotomy. A frozen section of lung tissue from the lesion demonstrated granulomatous inflammation. On the basis of this result, no additional lung material was resected. Gomori methenamine silver stain of the lung tissue demonstrated ovoid yeast cells (1.5 to 2.0 by 3.0 to 3.5
um).
What was your diagnosis and why did you determine this diagnosis? Why is the diagnosis of fungal diseases so difficult?
ANSWER 3.
4. What stain used on bone marrow specimens may also have detected the infectious agent?
ANSWER 4.
5. What subsequent cultures would you request? Why? How long would you expect it to take before the cultures grew from the clinical specimen and you could recover the organism? What would you expect the cultures to show?
ANSWER 5.
6. What are other dimorphic fungal pathogens? Do these pathogens grow quickly or slowly?
ANSWER 6.
7. In which areas of the United States is endemic for the disease you diagnosed? Where in nature is the organism found? What is the importance of obtaining a detailed travel history from your patient?
ANSWER 7.
8. What is the portal of entry in infection with this organism? Do you expect the infection to spread from this site? If so, to which organs?
ANSWER 8.
9. What immunity offers protection against the disease you diagnosed, and if compromised, can cause disseminated disease? What other causes of immunosuppression may also prevent the patient's immune system from controlling the infection?
ANSWER 9.
10. How would you treat the disease you diagnosed?
ANSWER 10.
CLINICAL CORRELATION:
Histoplasma capsulatum
is a dimorphic fungus that remains in a mycelial form at ambient temperatures and grows as yeast at body temperature in mammals. Although the fungus can be found in temperate climates throughout the world, it is endemic to the Ohio, Missouri, and Mississippi River valleys in the United States. Internationally, the fungus is predominantly found in river valleys between latitudes 45° north and 30° south in North and Central America.
The soil in endemic areas provides an acidic damp environment with high organic content that is good for mycelial growth. Highly infectious soil is found near areas inhabited by bats and birds. Birds cannot be infected by the fungus and do not transmit the disease; however, bird excretions contaminate the soil, thereby enriching the growth medium for the mycelium. In contrast, bats can become infected, and they transmit the fungus through droppings. Contaminated soil can be potentially infectious for years.
Most individuals who are infected are asymptomatic. Those who develop clinical manifestations are usually immunocompromised or are exposed to a high quantity of inoculum. Histoplasma species may remain latent in healed granulomas and recur, resulting in cell-mediated immunity impairment.
Pathophysiology
H capsulatum in the saprobic state grows in the mycelial form. Macroconidia and microconidia are produced on the hyphae of mycelium and are converted to the yeast form under temperature-controlled regulation. The aerosolization of conidia and mycelial fragments from contaminated soil results in alveolar deposition via inhalation.
The host defense includes the fungistatic properties of neutrophils and macrophages.
T lymphocytes are crucial in limiting the extent of infection. Susceptibility to dissemination is increased markedly with impaired cellular host defenses.
Conversion from the mycelial to the pathogenic yeast form occurs intracellularly. After phagocytosis by macrophages, the yeast replicates in approximately 15-18 hours. Despite fusion with lysosomes, multiplication continues within the phagosomes. Proposed theories suggest that the yeasts may produce proteins that inhibit the activity of lysosomal proteases.
As the host immunity response develops, yeast growth ceases within 1-2 weeks after exposure. Cytokines systemically activate the fungistatic activity of macrophages against intracellular yeasts. With further maturation of the cell-mediated response, delayed-type hypersensitivity to histoplasmal antigens occurs (3-6 wk after exposure). Approximately 85-90% of individuals who are immunocompetent produce a positive response to skin antigen test for Histoplasma species. Over weeks to months, the inflammatory response produces calcified granulomas with areas of caseous (TB-like) necrosis.
Clinical manifestations appear with continued exposure to large inocula. The initial pulmonary infection may disseminate systemically, with hematogenous spread, and produce extrapulmonary manifestations. Hematogenous spread to regional lymph nodes may occur through the lymphatics or the liver and spleen. Progressive disseminated histoplasmosis is rare in adult hosts who are immunocompetent. Systemic spread usually occurs in patients with impaired cellular immunity and typically involves the CNS, liver, spleen, and rheumatologic, ocular, and hematologic systems.
United
States
The central river valleys in the midwestern and south central United States are endemic for histoplasmosis. Approximately 250,000 individuals are infected annually. Clinical manifestations occur in less than 5% of the population.
Mortality/Morbidity
Morbidity and mortality are related to the duration and extent of systemic infection.
Approximately 90% of patients with acute pulmonary histoplasmosis are asymptomatic. Acute pericarditis can occur in as many as 5% of patients who are symptomatic. Pleural effusions develop in 40-60% of patients with pericarditis.
Chronic pulmonary histoplasmosis occurs in patients with underlying lung disease at a rate of 1 case per 100,000 persons per year in endemic areas. Approximately 90% of patients develop cavities that may enlarge and result in necrosis. Untreated cases may lead to progressive pulmonary fibrosis that results in respiratory and cardiac failure and recurrent infections.
Progressive disseminated histoplasmosis occurs in 1 case per 2000 cases in adults who are immunocompetent. This form occurs in 4-27% of infected individuals who are immunosuppressed, children, or older individuals. In the subacute form, death occurs within 2-24 months in untreated cases. Approximately 5-10% of patients, treated or not, develop adrenal insufficiency. The acute form, if untreated, results in death within weeks. Approximately 10% of individuals develop hyperacute syndrome, which results in death.
Although histoplasmosis can affect individuals of any age, those in extreme age ranges are more prone to developing infection as a result of immature or deteriorated immune defenses.
History
A thorough social and occupational history is essential in the initial evaluation. Travel or residence in an endemic area or activities involving bats or birds, whether recent or remote, should aid in the differential. Determine if the patient has a drug history or comorbid condition that is contributing to an immunocompromised state.
Approximately 90% of patients are asymptomatic. If symptoms develop, onset occurs 3-14 days after exposure. Fever, headache, malaise, myalgia, abdominal pain, and chills are common symptoms. Individuals exposed to a large inoculum may develop severe dyspnea resulting from diffuse pulmonary involvement.
Joint pain and skin lesions occur in 5-6% of patients, mostly in females.
Enlarged hilar and mediastinal lymph nodes are present in 5-10% of patients.
Occasionally, lymphadenopathy is significant enough to cause local obstructive syndromes. Superior vena cava (SVC) syndrome can occur with compression on the SVC. Significant obstruction of venous drainage may contribute to cerebral symptoms of headache, visual distortion, tinnitus, and altered consciousness.
Cough, hemoptysis, dyspnea, and/or chest pain may be present and are related to the degree of compression on the pulmonary airway and circulation. Paratracheal involvement may cause cough or dyspnea because of compression on the trachea or bronchi. Rarely, compression of the esophagus occurs, which causes dysphagia.
Chronic pulmonary histoplasmosis
This form occurs mostly in patients with underlying pulmonary disease and is associated with cough, weight loss, fevers, and malaise.
If cavitations are present, hemoptysis, sputum production, and increasing dyspnea are common symptoms.
Progressive disseminated histoplasmosis
This form occurs mostly in hosts who are immunocompromised. Symptoms vary depending on duration of illness.
The chronic form is associated with constitutional symptoms. Approximately 50-60% of patients have mouth and gum pain due to mucosal ulcers.
The subacute form is associated with a wide spectrum of symptoms that may occur as a result of dissemination and subacute expression in the affected organs. Aside from constitutional symptoms, gastrointestinal involvement may produce diarrhea and abdominal pain. Cardiac involvement resulting in valvular disease, cardiac insufficiency, or vegetations may produce dyspnea, peripheral edema, angina, and fever. CNS involvement may produce headache, visual and gait disturbances, confusion, seizures, altered consciousness, and neck stiffness or pain.
The acute form may produce fever, worsening cough, weight loss, malaise, and dyspnea. Approximately 5-20% of patients have CNS involvement.
Presumed ocular histoplasmosis syndrome
Approximately 1-10% of individuals living in endemic areas have ocular involvement that is usually asymptomatic.
Macula involvement may result in blindness.
Acute pulmonary histoplasmosis
Findings are usually minimal.
Auscultation may rarely reveal rales or wheezes. In cases with high innoculum, individuals may develop severe hypoxemia associated with rales that may mimic acute respiratory distress syndrome. Approximately 10% of patients have asymptomatic pleural effusions.
In 5% of patients, pericarditis may be present and can be associated with rubs.1 Cardiac tamponade is present in 40% of patients presenting with pericarditis.
Hepatosplenomegaly may occasionally be present.
Chronic pulmonary histoplasmosis: This form may manifest during pulmonary auscultation as nonspecific rales, wheezes, or findings consistent with the extent of underlying pneumonitis, consolidation, or cavitation.
Chronic progressive disseminated histoplasmosis
This condition may produce oropharyngeal ulcers involving the buccal mucosa, tongue, gingiva, and larynx. Lesions do not suggest dissemination. Rare cases of isolated lesions have been seen in individuals who are immunocompetent.
Subacute progressive disseminated histoplasmosis
Gastrointestinal dissemination may result in abdominal mass or intestinal ulcers and lesions. Surgical abdomen may result from intussusception, perforation, or obstruction.
CNS dissemination may produce findings associated with possible mass lesions or meningismus, including cranial nerve deficits, muscle weakness, ataxia, altered consciousness, or focal deficits.
Cardiac dissemination may result in signs and complications of endocarditis, including murmurs, peripheral edema, pulmonary rales or wheezes, petechia, or skin lesions.
Acute progressive disseminated histoplasmosis
CNS manifestations that include a mass lesion, encephalopathy, and meningitis (as observed in the subacute form) occur in 5-20% of patients.
Hepatosplenomegaly and lymphadenopathy are present in 30% of patients. SVC syndrome may be present with lymphadenopathy severe enough to cause obstruction. The resulting increased venous pressure may manifest as dilatation of collaterals in the neck and thorax; edema of the face, neck, and upper torso; and conjunctiva.
Cutaneous lesions are present in 10% of patients. Erythematous maculopapular lesions, ulcerations, purpura, and/or manifestations of endocarditis may be present. Oropharyngeal lesions may also be present.
Ocular histoplasmosis syndrome
Atrophic scars containing foci of lymphocytic cell infiltration termed histo spots may be present and are located posterior to the equator of the eye.
Approximately 10% of patients have bilateral involvement.
If the scars are located on the macula, retinal hemorrhage, detachment, or edema may be present.
Causes
The risk of infection is mostly related to environmental exposure and underlying immune status.
Endemic areas: Living in endemic areas with contaminated soil increases the risk of exposure.
Inoculum size
Individuals who are immunocompetent and exposed to a low inoculum of histoplasmosis are usually asymptomatic.
Inhalation of a large inoculum can cause diffuse pulmonary symptoms that may have a protracted course.
Immune status and comorbid factors
Reactivation, reinfection, or complications of infection usually occur in individuals who are immunocompromised or immunosuppressed.
Chronic pulmonary histoplasmosis is more prevalent in patients with underlying emphysema.
In acute progressive disseminated histoplasmosis, pancytopenia occurs in 70-90% of patients, with a platelet count less than 70,000. Pancytopenia may occur at a lower rate in chronic progressive disseminated histoplasmosis.
Alkaline phosphatase: Levels are elevated in acute progressive disseminated histoplasmosis and chronic pulmonary histoplasmosis.
Elevated LDH (lactic dehydrogenase) is often very high.( Normal Adult Range: 0 -
250 U/L Optimal Adult Reading: 125)
Sputum cultures
Positive yields occur in approximately 10-15% patients with acute pulmonary histoplasmosis.
Culture results are positive in 60% of specimens from patients with chronic pulmonary histoplasmosis.
Blood cultures
These findings are positive in 50-90% of patients with acute progressive disseminated histoplasmosis.
These findings are rarely positive in patients with other types of histoplasmosis.
Complement-fixing antibodies
Titer is considered positive at reciprocal dilutions greater than 1:8. A titer with dilutions greater than 1:32 suggests active histoplasmosis infection. Cross-reactivity with antigens from
Blastomyces dermatitidis and Coccidioides immitis may cause a false-positive test result.
Positive results are expected in 5-15% of cases of acute pulmonary infection 3 weeks after exposure. This figure increases to 75-95% at 6 weeks in cases of symptomatic infection. Test results usually normalize over months, with resolution of infection.
Test results may remain positive in 70-90% of cases associated with chronic pulmonary histoplasmosis or chronic progressive disseminated histoplasmosis.
Immunoprecipitating antibodies
This test detects antibodies to 2 glycoproteins, H and M.
Anti-M antibody is detected in 50-80% of patients and remains elevated for years.
Anti-H antibody is detected in only 10-20% of patients and becomes undetectable within 6 months in the absence of continued infection. Anti-H antibody is more specific for active histoplasmosis.
Serum and urine antigen detection.
These are useful in individuals who are immunocompromised when antibody production may be impaired.
Detection rates in cases of acute progressive disseminated histoplasmosis are 50% with serum assay and 90% with urine assay. Lower detection rates are observed in acute or chronic pulmonary histoplasmosis.
Cross-reactivity with Blastomyces and Coccidioides species causes false-positive results.
Some patients with acute histoplasmosis may have high serum levels of angiotensin-converting enzyme.3 This may cause a diagnostic confusion with sarcoidosis, particularly if the patient with histoplasmosis also has hilar adenopathy.
Imaging Studies
Chest radiography
In acute pulmonary histoplasmosis, findings on chest radiography are usually normal. Occasionally, hilar and mediastinal nodes are enlarged. Patchy infiltrates, predominately in the lower lung fields, may be present. In cases of exposure to high inoculum, diffuse pulmonary involvement correlates with a reticular nodular or miliary pattern on chest radiography. Pleural effusions are found in fewer than 10% of uncomplicated cases. Cavitations are rarely present.
Histoplasmomas are healed pulmonary lesions that appear as residual nodules on chest radiography. These coin lesions usually are 1-4 cm in diameter. When yeast forms are present in the core, continued fibrosis in response to the yeast antigens adds to the fibrotic capsule, slowly enlarging the lesions.
Hilar lymphadenopathy is rare in chronic pulmonary histoplasmosis, although calcified nodes from prior healed infections may be present. Cavitations, predominantly in the upper lobes, are present in 90% of patients. Underlying emphysematous changes are common. Progressive fibrotic scarring is present in long-standing cases.
In chronic progressive disseminated histoplasmosis, chest radiography findings usually do not reveal any active pulmonary disease.
In acute progressive disseminated histoplasmosis, hilar lymphadenopathy with diffuse nodular infiltrates is common, occurring in 50% of patients. Findings on chest radiography are normal in 33% of patients initially, but radiographs may reveal pulmonary involvement as the disease progresses.
Subacute progressive disseminated histoplasmosis results in adrenal infection in 80% of patients.
Tissue biopsy
Obtaining tissue from pulmonary lesions and lymph nodes by bronchoscopy, percutaneous needle biopsies, or rarely, thoracoscopy may be required to make the diagnosis.
Results of biopsy of oropharyngeal ulcers are usually diagnostic.
Pericardiocentesis
Pericarditis occurs in 10% of patients who are symptomatic. In 40% of these individuals, hemodynamic compromise may occur as a result of cardiac tamponade.
Cultures of pericardial fluid are rarely diagnostic.
Histologic Findings
Tissue biopsy results may reveal the presence of yeast forms in tissue through hematoxylin and eosin staining. Using the Grocott-Gomori methenamine-silver procedure, yeast may be detected in areas of caseation necrosis from histoplasmomas and calcified lymph nodes. Yeast forms in circulating neutrophils and monocytes are rarely detected using Wright-Giemsa staining. Most biopsies do not reveal organisms.
TREATMENT
Most infections in individuals who are immunocompetent are self-limiting and do not require therapy. In cases of prolonged infection, cases of systemic infection, or those involving individuals who are immunocompromised, medical treatment is recommended.
Treat acute pulmonary histoplasmosis as follows:
No treatment is required for individuals who are asymptomatic.
Monitor mild symptoms (without treatment).
In patients with prolonged symptoms or overwhelming pulmonary involvement, initiate medical therapy.
Treat chronic pulmonary histoplasmosis as follows:
No treatment is needed for asymptomatic immunocompetent individuals without serious underlying disease.
Observe mild interstitial pneumonitis and/or thin-walled (<3 mm) cavities with serial chest radiographs for 2-4 months. If the lesions are persistent, medical treatment is indicated. Patients with cavities with thick walls (>3 mm) or patients who are immunocompromised should receive medical treatment.
Persistent cavitations despite multiple courses of medical treatment warrant surgical consideration.
Initiate medical therapy for all patients with progressive disseminated histoplasmosis and meningitis. In severe cases of CNS infection, administer intrathecal or intraventricular injections in addition to intravenous antifungal therapy.
Severe disseminated histoplasmosis
Severe infection requires intravenous induction therapy with amphotericin B 0.7-1.0 mg/kg/d (or a lipid formulation 3-5 mg/kg/d). After 3-10 days of therapy and stabilization of the patient's clinical status, therapy may be switched to itraconazole 200 mg twice daily to complete 12 weeks of therapy. If itraconazole is not available or is not tolerated, fluconazole 800 mg orally once daily can be used as an alternative. (See "Treatment note" below regarding itraconazole and fluconazole.) CNS infection must be treated with a full course of amphotericin B, because of poor penetration of itraconazole into the CNS. Induction therapy must be followed by maintenance therapy (see below).
Maintenance/suppressive therapy
Lifelong maintenance therapy must be given to prevent relapse after the 12-week course of induction therapy and typically includes itraconazole 200 mg orally once daily or twice daily. Amphotericin B 50 mg once weekly or fluconazole 400-800 mg daily are alternatives for those who cannot tolerate or cannot obtain itraconazole. (See "Treatment note" below regarding itraconazole and fluconazole.)
It is not known whether maintenance therapy can be discontinued safely in patients who achieve immune reconstitution during antiretroviral therapy.
Itraconazole and fluconazole may cause fetal abnormalities if taken during the first trimester of pregnancy. Check pregnancy status in women of childbearing potential before starting these medications, and ensure that women are using appropriate birth control.
Hemodynamic and respiratory compromise from pericardial and pleural involvement warrants immediate procedural intervention. Perform thoracentesis or pericardiocentesis with severe pleural effusions and pericardial tamponade, respectively.
Cutaneous and rheumatologic lesions are self-limiting. Therapy is indicated only for prolonged episodes or in individuals who are immunosuppressed.
Treat extensive maculopathy in presumed ocular histoplasmosis with steroids.
Use surgical procedures for diagnostic purposes when other modalities are unrevealing. Intervention is also required when medical therapy is insufficient to alleviate the effects of progressive fibrosis, calcification, and scarring.
Thoracic surgery
In rare cases when serologic and procedural modalities cannot indicate a definitive diagnosis, consider obtaining sufficient tissue samples using thoracoscopy or by performing an open lung biopsy.
Surgical resection of pulmonary cavitary lesions is required when repeated relapses or progressive disease occurs despite repeated intensive medical therapy.
Progressive fibrosis of the mediastinum can produce traction or invade into adjacent structures and cause a distorted anatomy. Surgery with spiral vein grafts or vascular stents may be necessary to treat SVC syndrome associated with fibrosing mediastinitis. Surgery may also be required to alleviate scarring, to retain structural integrity, and to alleviate symptoms. The possibility of extensive adhesion and distortion associates surgery with high mortality rates.
Mechanical compression by mediastinal and hilar granulomatosis may require surgical excision. However, surgery is risky because of the possibility of spilling necrotic material into the mediastinum and initiating further fibrotic reaction. Patients may develop extensive symptoms from compression of pulmonary, vascular, and rarely, esophageal structures.
Endovascular histoplasmosis may result in infected valves and aneurysm formation, which requires surgical excision of infected valves and aneurysm repair. Treating endovascular histoplasmosis with medical therapy alone is rarely curative.
Ophthalmologic treatment 
Laser photocoagulation treatment may be needed in patients with active neovascular membrane formation due to choroiditis. Progressive vision loss may occur.
