Cleveland Clinic Journal of Medicine

The patient is started on ceftriaxone (Rocephin) and levofloxacin (Levaquin). Left thoracentesis reveals blood-tinged exudative pleural fluid with 1.01 × 10⁹/L nucleated cells, 43% neutrophils, 35% macrophages, and 15% lymphocytes; glucose and pH are normal. Pleural fluid culture is negative, and cytologic study does not reveal malignant cells. Computed tomography of the chest reveals consolidated pneumonia in the left upper lobe, with atelectasis of the left lower lobe and left pleural effusion. The combination of exudative pleural fluid with pH of 7.35, a glucose level of 87 mg/dL, a lactate dehydrogenase level of 406 U/L (normal range 100–200), negative microbiologic test results, and pneumonia supports the diagnosis of uncomplicated parapneumonic pleural effusion, which occurs in 40% of cases of bacterial pneumonia.

The patient could have been treated only for complicated left pneumonia with parapneumonic pleural effusion. But the high suspicion of foreign-body aspiration, with the history of mild mental retardation and previous recurrent right pneumonia, led to the further workup and appropriate treatment.

Risk factors for tracheobronchial foreign-body aspiration in adults are a depressed mental status or an impairment in the swallowing reflex.²

Aspiration commonly occurs into the right lung because of the almost straight axis between the trachea and the right mainstem bronchus.³ However, aspiration can occur into any part of the lung depending on the position of the patient. Common foreign bodies described in adults are teeth or dental appliances, pins, and semisolid food, especially in elderly people.⁴ The clinical presentation varies from dyspnea and wheezing to asphyxia and cardiac arrest. Unilateral wheezing—particularly in young children with asthma, cough, or cold symptoms—should raise suspicion of foreign body aspiration.

Delayed complications of bronchial obstruction manifest usually as pneumonia. Subsequently, pleural effusion may develop because of an increased capillary permeability secondary to endothelial injury,⁵ and may progress to empyema.

Fiberoptic bronchoscopy has become the cornerstone of the diagnostic evaluation in adults with suspected foreign-body aspiration. Treatment options include extraction of the foreign body via flexible bronchoscopy or rigid bronchoscopy. Rigid bronchoscopy has higher success rates but requires general anesthesia.⁶

A history of choking is not always obtained. Imaging studies do not localize the foreign body in all cases. Many other medical conditions mimic breathing abnormalities similar to those associated with tracheobronchial foreign body in adults. Only a high index of suspicion can ensure proper diagnosis and treatment.

The patient is started on ceftriaxone (Rocephin) and levofloxacin (Levaquin). Left thoracentesis reveals blood-tinged exudative pleural fluid with 1.01 × 10⁹/L nucleated cells, 43% neutrophils, 35% macrophages, and 15% lymphocytes; glucose and pH are normal. Pleural fluid culture is negative, and cytologic study does not reveal malignant cells. Computed tomography of the chest reveals consolidated pneumonia in the left upper lobe, with atelectasis of the left lower lobe and left pleural effusion. The combination of exudative pleural fluid with pH of 7.35, a glucose level of 87 mg/dL, a lactate dehydrogenase level of 406 U/L (normal range 100–200), negative microbiologic test results, and pneumonia supports the diagnosis of uncomplicated parapneumonic pleural effusion, which occurs in 40% of cases of bacterial pneumonia.

The patient could have been treated only for complicated left pneumonia with parapneumonic pleural effusion. But the high suspicion of foreign-body aspiration, with the history of mild mental retardation and previous recurrent right pneumonia, led to the further workup and appropriate treatment.

Risk factors for tracheobronchial foreign-body aspiration in adults are a depressed mental status or an impairment in the swallowing reflex.²

Aspiration commonly occurs into the right lung because of the almost straight axis between the trachea and the right mainstem bronchus.³ However, aspiration can occur into any part of the lung depending on the position of the patient. Common foreign bodies described in adults are teeth or dental appliances, pins, and semisolid food, especially in elderly people.⁴ The clinical presentation varies from dyspnea and wheezing to asphyxia and cardiac arrest. Unilateral wheezing—particularly in young children with asthma, cough, or cold symptoms—should raise suspicion of foreign body aspiration.

Delayed complications of bronchial obstruction manifest usually as pneumonia. Subsequently, pleural effusion may develop because of an increased capillary permeability secondary to endothelial injury,⁵ and may progress to empyema.

Fiberoptic bronchoscopy has become the cornerstone of the diagnostic evaluation in adults with suspected foreign-body aspiration. Treatment options include extraction of the foreign body via flexible bronchoscopy or rigid bronchoscopy. Rigid bronchoscopy has higher success rates but requires general anesthesia.⁶

A history of choking is not always obtained. Imaging studies do not localize the foreign body in all cases. Many other medical conditions mimic breathing abnormalities similar to those associated with tracheobronchial foreign body in adults. Only a high index of suspicion can ensure proper diagnosis and treatment.

The patient is started on ceftriaxone (Rocephin) and levofloxacin (Levaquin). Left thoracentesis reveals blood-tinged exudative pleural fluid with 1.01 × 10⁹/L nucleated cells, 43% neutrophils, 35% macrophages, and 15% lymphocytes; glucose and pH are normal. Pleural fluid culture is negative, and cytologic study does not reveal malignant cells. Computed tomography of the chest reveals consolidated pneumonia in the left upper lobe, with atelectasis of the left lower lobe and left pleural effusion. The combination of exudative pleural fluid with pH of 7.35, a glucose level of 87 mg/dL, a lactate dehydrogenase level of 406 U/L (normal range 100–200), negative microbiologic test results, and pneumonia supports the diagnosis of uncomplicated parapneumonic pleural effusion, which occurs in 40% of cases of bacterial pneumonia.

The patient could have been treated only for complicated left pneumonia with parapneumonic pleural effusion. But the high suspicion of foreign-body aspiration, with the history of mild mental retardation and previous recurrent right pneumonia, led to the further workup and appropriate treatment.

Risk factors for tracheobronchial foreign-body aspiration in adults are a depressed mental status or an impairment in the swallowing reflex.²

Aspiration commonly occurs into the right lung because of the almost straight axis between the trachea and the right mainstem bronchus.³ However, aspiration can occur into any part of the lung depending on the position of the patient. Common foreign bodies described in adults are teeth or dental appliances, pins, and semisolid food, especially in elderly people.⁴ The clinical presentation varies from dyspnea and wheezing to asphyxia and cardiac arrest. Unilateral wheezing—particularly in young children with asthma, cough, or cold symptoms—should raise suspicion of foreign body aspiration.

Delayed complications of bronchial obstruction manifest usually as pneumonia. Subsequently, pleural effusion may develop because of an increased capillary permeability secondary to endothelial injury,⁵ and may progress to empyema.

Fiberoptic bronchoscopy has become the cornerstone of the diagnostic evaluation in adults with suspected foreign-body aspiration. Treatment options include extraction of the foreign body via flexible bronchoscopy or rigid bronchoscopy. Rigid bronchoscopy has higher success rates but requires general anesthesia.⁶

A history of choking is not always obtained. Imaging studies do not localize the foreign body in all cases. Many other medical conditions mimic breathing abnormalities similar to those associated with tracheobronchial foreign body in adults. Only a high index of suspicion can ensure proper diagnosis and treatment.

A 19-year-old man received induction chemotherapy with idarubicin and cytarabine for secondary acute myeloid leukemia. Subsequently, he developed fever, progressive lung infiltrates, and severe neutropenia. His white blood cell count was 1.1 × 10⁹/L (reference range 4.0–11.0) with 100% lymphocytes; his blood glucose level remained normal.

The patient was treated with voriconazole (Vfend) and broad-spectrum antibiotics.

Q: Which is the most likely cause?

• A bacterium
• A virus
• Cryptococcus
• Aspergillus
• Zygomycetes

A: The correct answer is Zygomycetes, the second most common cause of fungal respiratory disease in patients with hematologic malignancies.

UNCOMMON BUT OFTEN FATAL

Zygomycetes is a class of fungi that contains two orders, Mucorales and Entomophthorales. Human disease, which is uncommon but frequently fatal, is predominantly associated with Mucorales and is commonly called mucormycosis.^1,2

The major mode of transmission is through inhalation of spores from diverse decaying environmental sources. As Zygomycetes are aerogenous pathogens, they predominantly affect the paranasal sinuses and the lungs. The main risk factors for Zygomycetes infection include diabetes mellitus, hematologic malignancies (predominantly acute leukemias treated with aggressive chemotherapeutic regimens), pharmacologic immunosuppression, solid organ or bone marrow transplantation, and therapy with deferoxamine (Desferal), an iron-chelating agent.^1,3

Overall, rhinocerebral disease is the most common manifestation, especially in the setting of diabetic ketoacidosis.¹ In hematologic malignancies, the most common presentation is pulmonary zygomycosis with associated profound neutropenia, as neutrophils are the central defense against filamentous fungal hyphae.^1,4

The incidence of zygomycosis is increasing, likely owing to the greater number of patients receiving stem cell or solid organ transplants, the use of more aggressive immunosuppressive regimens, prolonged survival, and the frequent prophylactic use of antifungal agents without activity against Zygomycetes.^2,5

INFECTION PROGRESSES RAPIDLY

Most patients present with fever, cough, thoracic pain, and dyspnea in association with hypoxemia and pulmonary infiltrates refractory to broad-spectrum antibiotics. Zygomycosis can also present radiographically as pulmonary nodules or consolidations with or without the halo sign or cavitations.^6,7

The disease usually progresses rapidly, invading vessels and causing infarction, bleeding, and dissemination to extrapulmonary sites.^1,5

In reported cases in patients with acute leukemia who received aggressive chemotherapy, the fungal infection occurred several days after profound neutropenia developed.^3,4

SPUTUM, LAVAGE, BIOPSY

The diagnosis is based on directly identifying the fungus morphologically and on culturing it. However, cultures of sputum, BAL fluid, and blood are usually negative.

Morphologically, the fungus is broad with irregular walls; it is also nearly aseptate and frequently has right-angle branching. In contrast, Aspergillus is narrow with parallel walls, distinctive septae, and acute branching.²

Of note: physicians need to alert the microbiology laboratory about their clinical suspicion of Zygomycetes infection, because the recovery rate of Zygomycetes in culture is increased by slicing the biopsy specimen in small pieces but not dicing it (to avoid breaking the septae).¹

The diagnostic tests include microscopic examination and culture of sputum, BAL fluid, and transbronchial biopsy specimens. If the initial tests are negative but the suspicion of zygomycosis is strong on clinical grounds, then fine-needle aspiration or open lung biopsy should be considered.¹

Useful predictors that favor the diagnosis of pulmonary zygomycosis instead of the main alternative, invasive pulmonary aspergillosis, include concomitant sinusitis, voriconazole prophylaxis (due to antifungal pressure), a negative galactomannan test in serum, multiple pulmonary nodules, and pleural effusion.^2,8

The treatment includes giving effective antifungal agents promptly, correcting hyperglycemia and metabolic acidosis, reversing immunosuppression (if possible), and considering surgical debridement.^1,2

Antifungal therapy is with conventional amphotericin B (Amphocin) or its lipid formulation (Abelcet). The lipid formulation is at least as effective as conventional amphotericin B and less nephrotoxic, thus allowing higher doses.^1,9 The optimal duration of therapy has not been evaluated, but experts in general treat until the pulmonary and sinus lesions have resolved.²

Posaconazole (Noxafil), a broad-spectrum oral azole, has activity in vitro and is a valuable alternative for patients who have refractory zygomycosis or who cannot tolerate amphotericin B.^5,10

The role of echinocandins is unclear, as they do not have in vitro activity against Zygomycetes. However, tests in animals have shown a synergistic effect between the echinocandin caspofungin (Cancidas) and amphotericin B lipid complex.¹¹ Other antifungal agents such as azoles lack activity against Zygomycetes.⁵

The return of neutrophils plays a substantial role in resolving the infection in neutropenic patients, a proposition supported by reports of the failure of antifungal therapy in patients with persistent neutropenia.¹ The addition of granulocyte colony-stimulating factor may accelerate neutrophil recovery and enhance neutrophil activity against opportunistic fungal pathogens.¹²

Even though progress has been made in the treatment of this disease, the prognosis continues to be poor in patients with hematologic malignancies and pulmonary or disseminated zygomycosis.⁹

ENDOBRONCHIAL ZYGOMYCOSIS

Aspergillosis is the most common endobronchial fungal disease. Zygomycosis is the third most common, after coccidioidomycosis. In zygomycosis, endobronchial lesions can be found in a third of patients who have pulmonary involvement.^6,13,14

The most common predisposing conditions for the development of endobronchial zygomycosis are diabetes and hematologic malignancies associated with neutropenia.¹⁴

Endobronchial zygomycosis is characterized by a locally invasive gray-white mucoid lesion that blocks a major airway.¹³ The involved airway is usually edematous and necrotic. The diagnosis can be made by visualizing the organism in bronchial washings, brushings, or endobronchial biopsies.¹⁴

If the disease is not promptly diagnosed, the risk of death is very high. The management includes high-dose conventional or lipid amphotericin B and surgical or endobronchial resection.^13,15

OUR CASE CONTINUED

After Zygomycetes was seen in the tissue from his bronchial biopsy, our patient received amphotericin B lipid complex at 5 mg/kg/day (started between images C and D in Figure 1). He had a good initial clinical response, but the infection progressed (image D in Figure 1).

The patient died as a result of massive hemoptysis attributable to the angioinvasive nature of the fungus, which most likely caused an erosion of a major pulmonary vessel.

TAKE-HOME POINTS

• Pulmonary disease is the most common manifestation of zygomycosis in patients with underlying hematologic malignancy. In this setting, zygomycosis has a high rate of morbidity and death.
• Endobronchial lesions can be seen in up to a third of patients with pulmonary zygomycosis.
• Prompt and effective therapy is essential for treatment to be successful.

A 19-year-old man received induction chemotherapy with idarubicin and cytarabine for secondary acute myeloid leukemia. Subsequently, he developed fever, progressive lung infiltrates, and severe neutropenia. His white blood cell count was 1.1 × 10⁹/L (reference range 4.0–11.0) with 100% lymphocytes; his blood glucose level remained normal.

The patient was treated with voriconazole (Vfend) and broad-spectrum antibiotics.

Q: Which is the most likely cause?

• A bacterium
• A virus
• Cryptococcus
• Aspergillus
• Zygomycetes

A: The correct answer is Zygomycetes, the second most common cause of fungal respiratory disease in patients with hematologic malignancies.

UNCOMMON BUT OFTEN FATAL

Zygomycetes is a class of fungi that contains two orders, Mucorales and Entomophthorales. Human disease, which is uncommon but frequently fatal, is predominantly associated with Mucorales and is commonly called mucormycosis.^1,2

The major mode of transmission is through inhalation of spores from diverse decaying environmental sources. As Zygomycetes are aerogenous pathogens, they predominantly affect the paranasal sinuses and the lungs. The main risk factors for Zygomycetes infection include diabetes mellitus, hematologic malignancies (predominantly acute leukemias treated with aggressive chemotherapeutic regimens), pharmacologic immunosuppression, solid organ or bone marrow transplantation, and therapy with deferoxamine (Desferal), an iron-chelating agent.^1,3

Overall, rhinocerebral disease is the most common manifestation, especially in the setting of diabetic ketoacidosis.¹ In hematologic malignancies, the most common presentation is pulmonary zygomycosis with associated profound neutropenia, as neutrophils are the central defense against filamentous fungal hyphae.^1,4

The incidence of zygomycosis is increasing, likely owing to the greater number of patients receiving stem cell or solid organ transplants, the use of more aggressive immunosuppressive regimens, prolonged survival, and the frequent prophylactic use of antifungal agents without activity against Zygomycetes.^2,5

INFECTION PROGRESSES RAPIDLY

Most patients present with fever, cough, thoracic pain, and dyspnea in association with hypoxemia and pulmonary infiltrates refractory to broad-spectrum antibiotics. Zygomycosis can also present radiographically as pulmonary nodules or consolidations with or without the halo sign or cavitations.^6,7

The disease usually progresses rapidly, invading vessels and causing infarction, bleeding, and dissemination to extrapulmonary sites.^1,5

In reported cases in patients with acute leukemia who received aggressive chemotherapy, the fungal infection occurred several days after profound neutropenia developed.^3,4

SPUTUM, LAVAGE, BIOPSY

The diagnosis is based on directly identifying the fungus morphologically and on culturing it. However, cultures of sputum, BAL fluid, and blood are usually negative.

Morphologically, the fungus is broad with irregular walls; it is also nearly aseptate and frequently has right-angle branching. In contrast, Aspergillus is narrow with parallel walls, distinctive septae, and acute branching.²

Of note: physicians need to alert the microbiology laboratory about their clinical suspicion of Zygomycetes infection, because the recovery rate of Zygomycetes in culture is increased by slicing the biopsy specimen in small pieces but not dicing it (to avoid breaking the septae).¹

The diagnostic tests include microscopic examination and culture of sputum, BAL fluid, and transbronchial biopsy specimens. If the initial tests are negative but the suspicion of zygomycosis is strong on clinical grounds, then fine-needle aspiration or open lung biopsy should be considered.¹

Useful predictors that favor the diagnosis of pulmonary zygomycosis instead of the main alternative, invasive pulmonary aspergillosis, include concomitant sinusitis, voriconazole prophylaxis (due to antifungal pressure), a negative galactomannan test in serum, multiple pulmonary nodules, and pleural effusion.^2,8

The treatment includes giving effective antifungal agents promptly, correcting hyperglycemia and metabolic acidosis, reversing immunosuppression (if possible), and considering surgical debridement.^1,2

Antifungal therapy is with conventional amphotericin B (Amphocin) or its lipid formulation (Abelcet). The lipid formulation is at least as effective as conventional amphotericin B and less nephrotoxic, thus allowing higher doses.^1,9 The optimal duration of therapy has not been evaluated, but experts in general treat until the pulmonary and sinus lesions have resolved.²

Posaconazole (Noxafil), a broad-spectrum oral azole, has activity in vitro and is a valuable alternative for patients who have refractory zygomycosis or who cannot tolerate amphotericin B.^5,10

The role of echinocandins is unclear, as they do not have in vitro activity against Zygomycetes. However, tests in animals have shown a synergistic effect between the echinocandin caspofungin (Cancidas) and amphotericin B lipid complex.¹¹ Other antifungal agents such as azoles lack activity against Zygomycetes.⁵

The return of neutrophils plays a substantial role in resolving the infection in neutropenic patients, a proposition supported by reports of the failure of antifungal therapy in patients with persistent neutropenia.¹ The addition of granulocyte colony-stimulating factor may accelerate neutrophil recovery and enhance neutrophil activity against opportunistic fungal pathogens.¹²

Even though progress has been made in the treatment of this disease, the prognosis continues to be poor in patients with hematologic malignancies and pulmonary or disseminated zygomycosis.⁹

ENDOBRONCHIAL ZYGOMYCOSIS

Aspergillosis is the most common endobronchial fungal disease. Zygomycosis is the third most common, after coccidioidomycosis. In zygomycosis, endobronchial lesions can be found in a third of patients who have pulmonary involvement.^6,13,14

The most common predisposing conditions for the development of endobronchial zygomycosis are diabetes and hematologic malignancies associated with neutropenia.¹⁴

Endobronchial zygomycosis is characterized by a locally invasive gray-white mucoid lesion that blocks a major airway.¹³ The involved airway is usually edematous and necrotic. The diagnosis can be made by visualizing the organism in bronchial washings, brushings, or endobronchial biopsies.¹⁴

If the disease is not promptly diagnosed, the risk of death is very high. The management includes high-dose conventional or lipid amphotericin B and surgical or endobronchial resection.^13,15

OUR CASE CONTINUED

After Zygomycetes was seen in the tissue from his bronchial biopsy, our patient received amphotericin B lipid complex at 5 mg/kg/day (started between images C and D in Figure 1). He had a good initial clinical response, but the infection progressed (image D in Figure 1).

The patient died as a result of massive hemoptysis attributable to the angioinvasive nature of the fungus, which most likely caused an erosion of a major pulmonary vessel.

TAKE-HOME POINTS

• Pulmonary disease is the most common manifestation of zygomycosis in patients with underlying hematologic malignancy. In this setting, zygomycosis has a high rate of morbidity and death.
• Endobronchial lesions can be seen in up to a third of patients with pulmonary zygomycosis.
• Prompt and effective therapy is essential for treatment to be successful.

A 19-year-old man received induction chemotherapy with idarubicin and cytarabine for secondary acute myeloid leukemia. Subsequently, he developed fever, progressive lung infiltrates, and severe neutropenia. His white blood cell count was 1.1 × 10⁹/L (reference range 4.0–11.0) with 100% lymphocytes; his blood glucose level remained normal.

The patient was treated with voriconazole (Vfend) and broad-spectrum antibiotics.

Q: Which is the most likely cause?

• A bacterium
• A virus
• Cryptococcus
• Aspergillus
• Zygomycetes

A: The correct answer is Zygomycetes, the second most common cause of fungal respiratory disease in patients with hematologic malignancies.

UNCOMMON BUT OFTEN FATAL

Zygomycetes is a class of fungi that contains two orders, Mucorales and Entomophthorales. Human disease, which is uncommon but frequently fatal, is predominantly associated with Mucorales and is commonly called mucormycosis.^1,2

The major mode of transmission is through inhalation of spores from diverse decaying environmental sources. As Zygomycetes are aerogenous pathogens, they predominantly affect the paranasal sinuses and the lungs. The main risk factors for Zygomycetes infection include diabetes mellitus, hematologic malignancies (predominantly acute leukemias treated with aggressive chemotherapeutic regimens), pharmacologic immunosuppression, solid organ or bone marrow transplantation, and therapy with deferoxamine (Desferal), an iron-chelating agent.^1,3

Overall, rhinocerebral disease is the most common manifestation, especially in the setting of diabetic ketoacidosis.¹ In hematologic malignancies, the most common presentation is pulmonary zygomycosis with associated profound neutropenia, as neutrophils are the central defense against filamentous fungal hyphae.^1,4

The incidence of zygomycosis is increasing, likely owing to the greater number of patients receiving stem cell or solid organ transplants, the use of more aggressive immunosuppressive regimens, prolonged survival, and the frequent prophylactic use of antifungal agents without activity against Zygomycetes.^2,5

INFECTION PROGRESSES RAPIDLY

Most patients present with fever, cough, thoracic pain, and dyspnea in association with hypoxemia and pulmonary infiltrates refractory to broad-spectrum antibiotics. Zygomycosis can also present radiographically as pulmonary nodules or consolidations with or without the halo sign or cavitations.^6,7

The disease usually progresses rapidly, invading vessels and causing infarction, bleeding, and dissemination to extrapulmonary sites.^1,5

In reported cases in patients with acute leukemia who received aggressive chemotherapy, the fungal infection occurred several days after profound neutropenia developed.^3,4

SPUTUM, LAVAGE, BIOPSY

The diagnosis is based on directly identifying the fungus morphologically and on culturing it. However, cultures of sputum, BAL fluid, and blood are usually negative.

Morphologically, the fungus is broad with irregular walls; it is also nearly aseptate and frequently has right-angle branching. In contrast, Aspergillus is narrow with parallel walls, distinctive septae, and acute branching.²

Of note: physicians need to alert the microbiology laboratory about their clinical suspicion of Zygomycetes infection, because the recovery rate of Zygomycetes in culture is increased by slicing the biopsy specimen in small pieces but not dicing it (to avoid breaking the septae).¹

The diagnostic tests include microscopic examination and culture of sputum, BAL fluid, and transbronchial biopsy specimens. If the initial tests are negative but the suspicion of zygomycosis is strong on clinical grounds, then fine-needle aspiration or open lung biopsy should be considered.¹

Useful predictors that favor the diagnosis of pulmonary zygomycosis instead of the main alternative, invasive pulmonary aspergillosis, include concomitant sinusitis, voriconazole prophylaxis (due to antifungal pressure), a negative galactomannan test in serum, multiple pulmonary nodules, and pleural effusion.^2,8

The treatment includes giving effective antifungal agents promptly, correcting hyperglycemia and metabolic acidosis, reversing immunosuppression (if possible), and considering surgical debridement.^1,2

Antifungal therapy is with conventional amphotericin B (Amphocin) or its lipid formulation (Abelcet). The lipid formulation is at least as effective as conventional amphotericin B and less nephrotoxic, thus allowing higher doses.^1,9 The optimal duration of therapy has not been evaluated, but experts in general treat until the pulmonary and sinus lesions have resolved.²

Posaconazole (Noxafil), a broad-spectrum oral azole, has activity in vitro and is a valuable alternative for patients who have refractory zygomycosis or who cannot tolerate amphotericin B.^5,10

The role of echinocandins is unclear, as they do not have in vitro activity against Zygomycetes. However, tests in animals have shown a synergistic effect between the echinocandin caspofungin (Cancidas) and amphotericin B lipid complex.¹¹ Other antifungal agents such as azoles lack activity against Zygomycetes.⁵

The return of neutrophils plays a substantial role in resolving the infection in neutropenic patients, a proposition supported by reports of the failure of antifungal therapy in patients with persistent neutropenia.¹ The addition of granulocyte colony-stimulating factor may accelerate neutrophil recovery and enhance neutrophil activity against opportunistic fungal pathogens.¹²

Even though progress has been made in the treatment of this disease, the prognosis continues to be poor in patients with hematologic malignancies and pulmonary or disseminated zygomycosis.⁹

ENDOBRONCHIAL ZYGOMYCOSIS

Aspergillosis is the most common endobronchial fungal disease. Zygomycosis is the third most common, after coccidioidomycosis. In zygomycosis, endobronchial lesions can be found in a third of patients who have pulmonary involvement.^6,13,14

The most common predisposing conditions for the development of endobronchial zygomycosis are diabetes and hematologic malignancies associated with neutropenia.¹⁴

Endobronchial zygomycosis is characterized by a locally invasive gray-white mucoid lesion that blocks a major airway.¹³ The involved airway is usually edematous and necrotic. The diagnosis can be made by visualizing the organism in bronchial washings, brushings, or endobronchial biopsies.¹⁴

If the disease is not promptly diagnosed, the risk of death is very high. The management includes high-dose conventional or lipid amphotericin B and surgical or endobronchial resection.^13,15

OUR CASE CONTINUED

After Zygomycetes was seen in the tissue from his bronchial biopsy, our patient received amphotericin B lipid complex at 5 mg/kg/day (started between images C and D in Figure 1). He had a good initial clinical response, but the infection progressed (image D in Figure 1).

The patient died as a result of massive hemoptysis attributable to the angioinvasive nature of the fungus, which most likely caused an erosion of a major pulmonary vessel.

TAKE-HOME POINTS

• Pulmonary disease is the most common manifestation of zygomycosis in patients with underlying hematologic malignancy. In this setting, zygomycosis has a high rate of morbidity and death.
• Endobronchial lesions can be seen in up to a third of patients with pulmonary zygomycosis.
• Prompt and effective therapy is essential for treatment to be successful.

But measurement of the blood pressure often stands alone, a physical measurement that may directly prompt therapy. We may listen for abdominal bruits, check the eye grounds, review an electrocardiogram, and measure electrolyte and creatinine levels looking for a cause of secondary hypertension or for end-organ damage. But in most cases, therapy ensues (or doesn’t) on the basis of readings from a low-tech sphygmomanometer.

We are often casual with how we measure blood pressure, despite its importance. For efficiency, in many offices, physician-extenders obtain a (single) measurement as the patient is being rushed into the examination room. We may recheck the pressure ourselves, but my conversations with many patients indicate that there is enormous variability in how the blood pressure is actually measured. Sometimes, the cuff is placed over a shirt, a large cuff is not appropriately used for a large arm, the cuff is not firmly inflated, or the pressure is not confirmed by dual measurement or checked in the contralateral arm or by palpation of the radial pulse. We should reflect upon the potential impact of these shortcuts.

Surprisingly, despite the many ways to introduce inaccuracies in low-tech cuff measurement of blood pressure, the benefits of treating high blood pressure diagnosed by these office measurements can be great. An excess of cardiovascular events can be linked to an elevation of even a few millimeters in the pressure. The benefit is even more surprising when we consider that intermittent office measurements do not tell us anything about the lability of the blood pressure or its circadian patterns, including during sleep.

In this issue of the Journal, Dr. Mohammad Rafey discusses alternative ways to measure the blood pressure, their strengths and their limitations. The concepts of abnormal “nocturnal dipping” and morning hypertensive surges will warrant far more attention as we use ambulatory 24-hour measurements and other techniques more frequently to augment the low-tech blood pressure check in the office.

But measurement of the blood pressure often stands alone, a physical measurement that may directly prompt therapy. We may listen for abdominal bruits, check the eye grounds, review an electrocardiogram, and measure electrolyte and creatinine levels looking for a cause of secondary hypertension or for end-organ damage. But in most cases, therapy ensues (or doesn’t) on the basis of readings from a low-tech sphygmomanometer.

We are often casual with how we measure blood pressure, despite its importance. For efficiency, in many offices, physician-extenders obtain a (single) measurement as the patient is being rushed into the examination room. We may recheck the pressure ourselves, but my conversations with many patients indicate that there is enormous variability in how the blood pressure is actually measured. Sometimes, the cuff is placed over a shirt, a large cuff is not appropriately used for a large arm, the cuff is not firmly inflated, or the pressure is not confirmed by dual measurement or checked in the contralateral arm or by palpation of the radial pulse. We should reflect upon the potential impact of these shortcuts.

Surprisingly, despite the many ways to introduce inaccuracies in low-tech cuff measurement of blood pressure, the benefits of treating high blood pressure diagnosed by these office measurements can be great. An excess of cardiovascular events can be linked to an elevation of even a few millimeters in the pressure. The benefit is even more surprising when we consider that intermittent office measurements do not tell us anything about the lability of the blood pressure or its circadian patterns, including during sleep.

In this issue of the Journal, Dr. Mohammad Rafey discusses alternative ways to measure the blood pressure, their strengths and their limitations. The concepts of abnormal “nocturnal dipping” and morning hypertensive surges will warrant far more attention as we use ambulatory 24-hour measurements and other techniques more frequently to augment the low-tech blood pressure check in the office.

But measurement of the blood pressure often stands alone, a physical measurement that may directly prompt therapy. We may listen for abdominal bruits, check the eye grounds, review an electrocardiogram, and measure electrolyte and creatinine levels looking for a cause of secondary hypertension or for end-organ damage. But in most cases, therapy ensues (or doesn’t) on the basis of readings from a low-tech sphygmomanometer.

We are often casual with how we measure blood pressure, despite its importance. For efficiency, in many offices, physician-extenders obtain a (single) measurement as the patient is being rushed into the examination room. We may recheck the pressure ourselves, but my conversations with many patients indicate that there is enormous variability in how the blood pressure is actually measured. Sometimes, the cuff is placed over a shirt, a large cuff is not appropriately used for a large arm, the cuff is not firmly inflated, or the pressure is not confirmed by dual measurement or checked in the contralateral arm or by palpation of the radial pulse. We should reflect upon the potential impact of these shortcuts.

Surprisingly, despite the many ways to introduce inaccuracies in low-tech cuff measurement of blood pressure, the benefits of treating high blood pressure diagnosed by these office measurements can be great. An excess of cardiovascular events can be linked to an elevation of even a few millimeters in the pressure. The benefit is even more surprising when we consider that intermittent office measurements do not tell us anything about the lability of the blood pressure or its circadian patterns, including during sleep.

In this issue of the Journal, Dr. Mohammad Rafey discusses alternative ways to measure the blood pressure, their strengths and their limitations. The concepts of abnormal “nocturnal dipping” and morning hypertensive surges will warrant far more attention as we use ambulatory 24-hour measurements and other techniques more frequently to augment the low-tech blood pressure check in the office.

A 66-year-old Korean man presented with a 2-week history of progressive jaundice, mild epigastric discomfort, and a weight loss of 12 lb. His serum bilirubin level was 5.8 mg/dL (reference range 0.0–1.5), and his alkaline phosphatase level was 325 U/L (20–120). Computed tomography (CT) revealed a 3-cm mass in the head of the pancreas.

Exploratory laparotomy revealed a fibrotic pancreas with a palpable mass in the pancreatic head. The mass was unresectable, as it was adhering to the portal vein. A choledochoduodenostomy (anastamosis of the common bile duct to the duodenum) was created for palliation of jaundice. Intraoperative core biopsy revealed destruction of the pancreatic acinar architecture by marked lymphoplasmacytic inflammation and lymphocytic and obliterative venulitis, consistent with autoimmune pancreatitis.

Immediately after surgery, his serum immunoglobulin G4 (IgG4) level was 380 mg/dL (reference range 1–112). His bilirubin and alkaline phosphatase values came down into the normal range in the immediate postoperative period, and his jaundice resolved after a few days.

A CHRONIC INFLAMMATORY CONDITION

Autoimmune pancreatitis is a chronic inflammatory condition with distinct clinical, radiographic, and histologic features.

Sarles et al,¹ in 1961, were first to propose that autoimmunity may be a factor in chronic pancreatitis. Three decades later, autoimmune pancreatitis was codified as a separate disease on the basis of a case report of a patient with serum elevations of IgG and gamma globulin, pancreatic duct narrowing, lymphocytic infiltration, fibrosis, and a marked response to steroid therapy.² Yet its pathogenesis remains poorly understood.

Extrapancreatic manifestations include sclerosing sialadenitis, sclerosing cholangitis, and retroperitoneal fibrosis.

Of note, autoimmune pancreatitis can mimic pancreatic adenocarcinoma clinically and radiographically. One must differentiate between the two disorders to prevent unnecessary surgery or delay in corticosteroid therapy.

RATES ARE POORLY DEFINED

The exact prevalence and incidence of autoimmune pancreatitis remain poorly defined. Most of the initial epidemiologic data have come from Japan and Korea. The prevalence was 0.7 per 100,000 patients in a survey of the Japanese population.³ Further studies are needed to ascertain its incidence and prevalence in the United States.

In patients with chronic pancreatitis, the estimated prevalence is between 4.6% and 6%, and 11% in patients undergoing pancreatic resection for suspected pancreatic cancer.^4,5

Autoimmune pancreatitis appears to be a disease of the elderly, as most patients are more than 50 years old at diagnosis. Twice as many men as women are affected.⁵ Many patients have no history of alcohol abuse or other traditional risk factors for chronic pancreatitis.

CLINICAL PRESENTATION: PAINLESS JAUNDICE, WEIGHT LOSS

The most common clinical presentation is obstructive jaundice with little or no abdominal pain. In one series,⁴ 65% of patients presented with painless jaundice secondary to biliary obstruction. Obstructive acute pancreatitis can occur, due to inflammatory strictures of the main pancreatic duct.

Weight loss results from impaired digestion and decreased appetite. Autoimmune pancreatitis is complicated by pancreatic exocrine insufficiency in 88% of cases⁶ and by endocrine dysfunction in 67%.³

Many patients have extrapancreatic lesions such as sclerosing sialadenitis, retroperitoneal fibrosis, and autoimmune sclerosing cholangitis.⁷ The cholangiographic appearance of autoimmune sclerosing cholangitis may resemble that of primary sclerosing cholangitis or cholangiocarcinoma. Less common extrapancreatic findings include interstitial nephritis and mediastinal adenopathy. These extrapancreatic findings do not always coincide with pancreatic inflammation. The histopathologic findings in extrapancreatic lesions parallel those in the pancreas.⁸

The patient described at the beginning of this article had several of these features, including painless jaundice, weight loss, elevated alkaline phosphatase, and an inflammatory pancreatic mass.

DIAGNOSIS IS IMPROVING

Laboratory findings

Serum amylase and lipase are neither sensitive nor specific for autoimmune pancreatitis. Usually, their values are within normal limits or only mildly elevated.

A cholestatic pattern of elevation (elevated alkaline phosphatase and bilirubin, with normal or only slightly elevated alanine and aspartate aminotransferases) is found in patients with an inflammatory mass in the pancreatic head and in those with autoimmune sclerosing cholangitis. In one series,⁴ pancreatic enzymes were elevated in only 3 (13%) of 17 cases, while cholestasis was present in 16 (94%).

Gamma globulin, total IgG, and IgG4 are commonly elevated in autoimmune pancreatitis. Serum IgG4 is considered the most sensitive and specific marker and is elevated in 63% to 94% of patients with autoimmune pancreatitis.^4,15–17 Several studies found the diagnostic accuracy, sensitivity, and specificity to be highest (> 90%) when a cut point of 135 mg/dL was used.^17,18 A subsequent study ¹⁵ revealed a sensitivity of 76% and a specificity of 93% using the same cut point. Recall that the IgG4 level in our patient was 380 mg/dL.

Autoantibodies that are elevated in autoimmune pancreatitis include antilactoferrin antibodies and anticarbonic anhydrase II antibodies. ¹⁹ Both are “organ-specific”: the former are found in pancreatic acinar cells, and the latter are found in ductal cells. The sensitivity of both antibodies is greater than 50% in patients with autoimmune pancreatitis. However, they are not often measured, since testing for them is not widely available.^20,21

Antinuclear antibody and rheumatoid factor are also associated with autoimmune pancreatitis but are not very specific.

Radiographic findings

The most common radiographic feature is diffuse enlargement of the entire pancreas. The appearance of the gland is often described as “sausage-like,” a feature best seen with CT and magnetic resonance imaging (MRI).

A well-defined capsule-like rim surrounding the pancreas is another common feature.²³ This rim-enhancement is hypointense on T2 MRI, suggesting the presence of peripheral inflammation and fibrosis.

Calcifications and pseudocysts are rarely seen in autoimmune pancreatitis.

On ultrasonography, the involved pancreatic parenchyma appears hypoechoic, consistent with edema.

Endoscopic retrograde cholangiopancreatography

ERCP or magnetic resonance cholangiopancreatography may reveal segmental or diffuse narrowing of the main pancreatic duct.^24,25 Bile-duct strictures may occur throughout the biliary tree.²³

Autoimmune pancreatitis with biliary involvement must be distinguished from primary sclerosing cholangitis because the former responds to corticosteroid treatment. Cholangiographic features in primary sclerosing cholangitis include band-like strictures and a beaded or “pruned-tree” appearance, while autoimmune pancreatitis more commonly produces long strictures with prestenotic dilatation.²⁶

ERCP allows temporary stents to be placed in obstructed segments of the biliary tree to open them up in the setting of acute cholangitis.

Biopsy guided by endoscopic ultrasonography

Some have proposed using endoscopic ultrasonography to guide biopsy in cases of suspected autoimmune pancreatitis.^27,28

Fine-needle aspiration biopsy, guided by endoscopic ultrasonography, is frequently used to rule out adenocarcinoma. However, its yield for cancer is not perfect (about 70%–90%), so a negative biopsy does not rule out cancer. Further, autoimmune pancreatitis is rare, so a patient with a negative finding on fine-needle aspiration biopsy is still more likely to have cancer than autoimmune pancreatitis. In this case, the negative study should be combined with other information (eg, IgG4) to decide whether empiric treatment should be given.

Core biopsy, also guided by endoscopic ultrasonography, collects a greater amount of tissue for analysis and may allow the histologic diagnosis of autoimmune pancreatitis, but it carries a greater risk of bleeding. Also, its yield may be lower than initially thought. In one series, only 26% of ultrasonographically guided core samples from patients with confirmed autoimmune pancreatitis had diagnostic histologic features.²⁹

New immunohistologic techniques are being developed to increase the yield from cytologic and tissue specimens.