The Clinical Picture

A 60-year-old man with mild mental retardation, hypertension, chronic obstructive pulmonary disease, and recurrent left-sided pneumonia presents with worsening shortness of breath and productive cough. No fever, chills, or weight loss are noted. The physical examination reveals decreased air entry on the left side. His white blood cell count is 13.0 × 10⁹/L (normal range 4.5–11.0), with 90% neutrophils. Chest radiography (Figure 1) shows moderate left pleural effusion and left basilar infiltrate.

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.

Flexible bronchoscopy revealed an occlusive foreign body—a candy wrapper (Figure 2)—in the distal left mainstem bronchus, and this was successfully removed.¹

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 60-year-old man with mild mental retardation, hypertension, chronic obstructive pulmonary disease, and recurrent left-sided pneumonia presents with worsening shortness of breath and productive cough. No fever, chills, or weight loss are noted. The physical examination reveals decreased air entry on the left side. His white blood cell count is 13.0 × 10⁹/L (normal range 4.5–11.0), with 90% neutrophils. Chest radiography (Figure 1) shows moderate left pleural effusion and left basilar infiltrate.

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.

Flexible bronchoscopy revealed an occlusive foreign body—a candy wrapper (Figure 2)—in the distal left mainstem bronchus, and this was successfully removed.¹

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 60-year-old man with mild mental retardation, hypertension, chronic obstructive pulmonary disease, and recurrent left-sided pneumonia presents with worsening shortness of breath and productive cough. No fever, chills, or weight loss are noted. The physical examination reveals decreased air entry on the left side. His white blood cell count is 13.0 × 10⁹/L (normal range 4.5–11.0), with 90% neutrophils. Chest radiography (Figure 1) shows moderate left pleural effusion and left basilar infiltrate.

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.

Flexible bronchoscopy revealed an occlusive foreign body—a candy wrapper (Figure 2)—in the distal left mainstem bronchus, and this was successfully removed.¹

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 admitted to the hospital. Bronchoscopy showed the airways to be normal, but the bronchoalveolar lavage (BAL) fluid contained an elevated number of white blood cells, predominantly monocytes. A galactomannan antigen test (a test for Aspergillus) of the BAL fluid gave a result of 0.7 (a positive result is ≥ 0.5). Cultures of the BAL fluid and of transbronchial biopsy specimens were negative for bacteria and fungi. A galactomannan test of the blood was negative at 0.24.

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

In the next month and a half, serial computed tomographic scans of the chest were performed (Figure 1). The patient underwent bronchoscopy again (between images C and D in Figure 1), which revealed an endobronchial lesion in the right upper lobe that had not been seen before (Figure 2). A bronchial biopsy specimen was examined microscopically with Gomori methenamine silver staining (Figure 3). A galactomannan test of the second BAL specimen was negative.

After the second bronchoscopy, appropriate therapy was started, but the patient died after 2 months in the hospital as a result of massive hemoptysis.

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

 

 

TREATMENT WITH AMPHOTERICIN

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 admitted to the hospital. Bronchoscopy showed the airways to be normal, but the bronchoalveolar lavage (BAL) fluid contained an elevated number of white blood cells, predominantly monocytes. A galactomannan antigen test (a test for Aspergillus) of the BAL fluid gave a result of 0.7 (a positive result is ≥ 0.5). Cultures of the BAL fluid and of transbronchial biopsy specimens were negative for bacteria and fungi. A galactomannan test of the blood was negative at 0.24.

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

In the next month and a half, serial computed tomographic scans of the chest were performed (Figure 1). The patient underwent bronchoscopy again (between images C and D in Figure 1), which revealed an endobronchial lesion in the right upper lobe that had not been seen before (Figure 2). A bronchial biopsy specimen was examined microscopically with Gomori methenamine silver staining (Figure 3). A galactomannan test of the second BAL specimen was negative.

After the second bronchoscopy, appropriate therapy was started, but the patient died after 2 months in the hospital as a result of massive hemoptysis.

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

 

 

TREATMENT WITH AMPHOTERICIN

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 admitted to the hospital. Bronchoscopy showed the airways to be normal, but the bronchoalveolar lavage (BAL) fluid contained an elevated number of white blood cells, predominantly monocytes. A galactomannan antigen test (a test for Aspergillus) of the BAL fluid gave a result of 0.7 (a positive result is ≥ 0.5). Cultures of the BAL fluid and of transbronchial biopsy specimens were negative for bacteria and fungi. A galactomannan test of the blood was negative at 0.24.

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

In the next month and a half, serial computed tomographic scans of the chest were performed (Figure 1). The patient underwent bronchoscopy again (between images C and D in Figure 1), which revealed an endobronchial lesion in the right upper lobe that had not been seen before (Figure 2). A bronchial biopsy specimen was examined microscopically with Gomori methenamine silver staining (Figure 3). A galactomannan test of the second BAL specimen was negative.

After the second bronchoscopy, appropriate therapy was started, but the patient died after 2 months in the hospital as a result of massive hemoptysis.

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

 

 

TREATMENT WITH AMPHOTERICIN

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 66-year-old white man presents with a 1-month history of two nontender, nonpruritic skin lesions on his leg 3 weeks after undergoing bilateral lung transplantation for idiopathic pulmonary fibrosis (Figure 1). Except for transient lymphopenia, the postoperative course has been uneventful, with no episodes of rejection. Immunosuppressive drugs include tacrolimus (Prograf) and steroids. He has a history of insulin-dependent diabetes mellitus, and no history of significant trauma to his legs. Other than the skin lesions, he feels well and has no systemic symptoms. He has no history of iron overload or deferoxamine (Desferal) therapy.

Q: What is the probable diagnosis?

• Kaposi sarcoma
• Majocchi (trichophytic) granuloma
• Staphylococcus aureus furunculosis
• Primary cutaneous mucormycosis
• Disseminated zoster

A: This patient has primary cutaneous mucormycosis. Microscopic examination of the skin biopsy showed suppurative granulomatous inflammation with numerous nonseptated, branching fungal hyphae (Figure 2). A fungal culture grew Absidia species. No evidence of disseminated disease was found on computed tomography of the brain, paranasal sinuses, chest, abdomen, and pelvis. Histologic studies and cultures taken from both native and transplanted lungs were negative for fungi.

CAUSES AND RISK FACTORS

Mucormycosis is an invasive infection caused by fungi of a variety of genera (Rhizopus, Rhizomucor, Mucor, Absidia, Apophysomyces, Cunninghamella, Saksenaea, Conidiobolus, and Basidiobolus species) belonging to the class Zygomycetes in the order Mucorales. These ubiquitous environmental fungi have been found widely distributed in hospital sources, having been cultured from plaster casts,¹ tongue depressors,² cloth tapes for securing endotracheal tubes,³ peritoneal dialysis catheters,⁴ surgical wounds,⁵ contaminated dressings, needles, and intravenous catheters.⁶

These fungi rarely cause disease in healthy people, but patients with certain risk factors may develop disseminated disease, in which the death rate is high.⁶ Risk factors include diabetes mellitus, renal failure, trauma, burns, malnutrition, solid organ transplantation, hematologic malignancies, use of immunosuppressive drugs (eg, chemotherapeutic agents, corticosteroids, cyclosporine, methotrexate, infliximab [Remicade]⁷), and iron overload and iron-chelating therapy with deferoxamine. ⁸ Patients such as ours—an organ transplant recipient with concomitant diabetes mellitus—are highly susceptible to this infection.

DIAGNOSIS

The clinical presentation of mucormycosis can be rhino-orbitocerebral (most common),⁹ pulmonary, primary cutaneous, gastrointestinal, cardiac, or disseminated infection.⁶ Primary cutaneous mucormycosis occurs from fungal inoculation of the dermis. Small areas of trauma may be all that is needed for this inoculation to occur.

The initial lesion may be an erythematous patch, plaque, or nodule that may subsequently ulcerate and become gangrenous or necrotic.¹⁰

The differential diagnosis of new cutaneous nodules in an immunocompromised patient includes a wide variety of infections, such as ecthyma gangrenosum caused by Pseudomonas or Candida species, herpes simplex virus infection, cryptococcal infection, phaeohyphomycosis, and cutaneous aspergillosis.

Because the morphology of cutaneous mucormycosis is not distinctive, and because we need to cast our net wide for the numerous, potentially lethal diagnostic possibilities in an immunosuppressed patient, it is crucial that we have a low threshold for prompt biopsy to establish the diagnosis and initiate definitive treatment. While skin biopsy for microscopy can suggest certain fungi, the exact diagnosis is confirmed by a fungal culture of a biopsy specimen.

TREATMENT

Localized soft tissue infection is more amenable to therapy and therefore carries a better prognosis than visceral or disseminated disease.

The best treatment outcomes of primary cutaneous mucormycosis are achieved with both complete excision and debridement of necrotic tissue and systemic antifungal therapy. Amphotericin B in conventional form (Fungizone) and liposomal form (AmBisome) and posaconazole (Noxafil)^11–12 are effective.

Paradoxically, in contrast to deferoxamine, other iron chelators such as deferiprone (Ferriprox, not available in the United States) and deferasirox (Exjade), which do not supply iron to the fungus, had been shown to be effective against Zygomycetes in in vitro and animal models. The role of iron chelators as adjunctive therapy for mucormycosis needs further investigation.⁸

Primary cutaneous mucormycosis may become a disseminated infection. Therefore, one should have a high index of suspicion. When a transplant recipient develops a cutaneous plaque or nodule, biopsy should be performed promptly. Failure to do so can increase the risk of morbidity and death.

A 66-year-old white man presents with a 1-month history of two nontender, nonpruritic skin lesions on his leg 3 weeks after undergoing bilateral lung transplantation for idiopathic pulmonary fibrosis (Figure 1). Except for transient lymphopenia, the postoperative course has been uneventful, with no episodes of rejection. Immunosuppressive drugs include tacrolimus (Prograf) and steroids. He has a history of insulin-dependent diabetes mellitus, and no history of significant trauma to his legs. Other than the skin lesions, he feels well and has no systemic symptoms. He has no history of iron overload or deferoxamine (Desferal) therapy.

Q: What is the probable diagnosis?

• Kaposi sarcoma
• Majocchi (trichophytic) granuloma
• Staphylococcus aureus furunculosis
• Primary cutaneous mucormycosis
• Disseminated zoster

A: This patient has primary cutaneous mucormycosis. Microscopic examination of the skin biopsy showed suppurative granulomatous inflammation with numerous nonseptated, branching fungal hyphae (Figure 2). A fungal culture grew Absidia species. No evidence of disseminated disease was found on computed tomography of the brain, paranasal sinuses, chest, abdomen, and pelvis. Histologic studies and cultures taken from both native and transplanted lungs were negative for fungi.

CAUSES AND RISK FACTORS

Mucormycosis is an invasive infection caused by fungi of a variety of genera (Rhizopus, Rhizomucor, Mucor, Absidia, Apophysomyces, Cunninghamella, Saksenaea, Conidiobolus, and Basidiobolus species) belonging to the class Zygomycetes in the order Mucorales. These ubiquitous environmental fungi have been found widely distributed in hospital sources, having been cultured from plaster casts,¹ tongue depressors,² cloth tapes for securing endotracheal tubes,³ peritoneal dialysis catheters,⁴ surgical wounds,⁵ contaminated dressings, needles, and intravenous catheters.⁶

These fungi rarely cause disease in healthy people, but patients with certain risk factors may develop disseminated disease, in which the death rate is high.⁶ Risk factors include diabetes mellitus, renal failure, trauma, burns, malnutrition, solid organ transplantation, hematologic malignancies, use of immunosuppressive drugs (eg, chemotherapeutic agents, corticosteroids, cyclosporine, methotrexate, infliximab [Remicade]⁷), and iron overload and iron-chelating therapy with deferoxamine. ⁸ Patients such as ours—an organ transplant recipient with concomitant diabetes mellitus—are highly susceptible to this infection.

DIAGNOSIS

The clinical presentation of mucormycosis can be rhino-orbitocerebral (most common),⁹ pulmonary, primary cutaneous, gastrointestinal, cardiac, or disseminated infection.⁶ Primary cutaneous mucormycosis occurs from fungal inoculation of the dermis. Small areas of trauma may be all that is needed for this inoculation to occur.

The initial lesion may be an erythematous patch, plaque, or nodule that may subsequently ulcerate and become gangrenous or necrotic.¹⁰

The differential diagnosis of new cutaneous nodules in an immunocompromised patient includes a wide variety of infections, such as ecthyma gangrenosum caused by Pseudomonas or Candida species, herpes simplex virus infection, cryptococcal infection, phaeohyphomycosis, and cutaneous aspergillosis.

Because the morphology of cutaneous mucormycosis is not distinctive, and because we need to cast our net wide for the numerous, potentially lethal diagnostic possibilities in an immunosuppressed patient, it is crucial that we have a low threshold for prompt biopsy to establish the diagnosis and initiate definitive treatment. While skin biopsy for microscopy can suggest certain fungi, the exact diagnosis is confirmed by a fungal culture of a biopsy specimen.

TREATMENT

Localized soft tissue infection is more amenable to therapy and therefore carries a better prognosis than visceral or disseminated disease.

The best treatment outcomes of primary cutaneous mucormycosis are achieved with both complete excision and debridement of necrotic tissue and systemic antifungal therapy. Amphotericin B in conventional form (Fungizone) and liposomal form (AmBisome) and posaconazole (Noxafil)^11–12 are effective.

Paradoxically, in contrast to deferoxamine, other iron chelators such as deferiprone (Ferriprox, not available in the United States) and deferasirox (Exjade), which do not supply iron to the fungus, had been shown to be effective against Zygomycetes in in vitro and animal models. The role of iron chelators as adjunctive therapy for mucormycosis needs further investigation.⁸

Primary cutaneous mucormycosis may become a disseminated infection. Therefore, one should have a high index of suspicion. When a transplant recipient develops a cutaneous plaque or nodule, biopsy should be performed promptly. Failure to do so can increase the risk of morbidity and death.

A 66-year-old white man presents with a 1-month history of two nontender, nonpruritic skin lesions on his leg 3 weeks after undergoing bilateral lung transplantation for idiopathic pulmonary fibrosis (Figure 1). Except for transient lymphopenia, the postoperative course has been uneventful, with no episodes of rejection. Immunosuppressive drugs include tacrolimus (Prograf) and steroids. He has a history of insulin-dependent diabetes mellitus, and no history of significant trauma to his legs. Other than the skin lesions, he feels well and has no systemic symptoms. He has no history of iron overload or deferoxamine (Desferal) therapy.

Q: What is the probable diagnosis?

• Kaposi sarcoma
• Majocchi (trichophytic) granuloma
• Staphylococcus aureus furunculosis
• Primary cutaneous mucormycosis
• Disseminated zoster

A: This patient has primary cutaneous mucormycosis. Microscopic examination of the skin biopsy showed suppurative granulomatous inflammation with numerous nonseptated, branching fungal hyphae (Figure 2). A fungal culture grew Absidia species. No evidence of disseminated disease was found on computed tomography of the brain, paranasal sinuses, chest, abdomen, and pelvis. Histologic studies and cultures taken from both native and transplanted lungs were negative for fungi.

CAUSES AND RISK FACTORS

Mucormycosis is an invasive infection caused by fungi of a variety of genera (Rhizopus, Rhizomucor, Mucor, Absidia, Apophysomyces, Cunninghamella, Saksenaea, Conidiobolus, and Basidiobolus species) belonging to the class Zygomycetes in the order Mucorales. These ubiquitous environmental fungi have been found widely distributed in hospital sources, having been cultured from plaster casts,¹ tongue depressors,² cloth tapes for securing endotracheal tubes,³ peritoneal dialysis catheters,⁴ surgical wounds,⁵ contaminated dressings, needles, and intravenous catheters.⁶

These fungi rarely cause disease in healthy people, but patients with certain risk factors may develop disseminated disease, in which the death rate is high.⁶ Risk factors include diabetes mellitus, renal failure, trauma, burns, malnutrition, solid organ transplantation, hematologic malignancies, use of immunosuppressive drugs (eg, chemotherapeutic agents, corticosteroids, cyclosporine, methotrexate, infliximab [Remicade]⁷), and iron overload and iron-chelating therapy with deferoxamine. ⁸ Patients such as ours—an organ transplant recipient with concomitant diabetes mellitus—are highly susceptible to this infection.

DIAGNOSIS

The clinical presentation of mucormycosis can be rhino-orbitocerebral (most common),⁹ pulmonary, primary cutaneous, gastrointestinal, cardiac, or disseminated infection.⁶ Primary cutaneous mucormycosis occurs from fungal inoculation of the dermis. Small areas of trauma may be all that is needed for this inoculation to occur.

The initial lesion may be an erythematous patch, plaque, or nodule that may subsequently ulcerate and become gangrenous or necrotic.¹⁰

The differential diagnosis of new cutaneous nodules in an immunocompromised patient includes a wide variety of infections, such as ecthyma gangrenosum caused by Pseudomonas or Candida species, herpes simplex virus infection, cryptococcal infection, phaeohyphomycosis, and cutaneous aspergillosis.

Because the morphology of cutaneous mucormycosis is not distinctive, and because we need to cast our net wide for the numerous, potentially lethal diagnostic possibilities in an immunosuppressed patient, it is crucial that we have a low threshold for prompt biopsy to establish the diagnosis and initiate definitive treatment. While skin biopsy for microscopy can suggest certain fungi, the exact diagnosis is confirmed by a fungal culture of a biopsy specimen.

TREATMENT

Localized soft tissue infection is more amenable to therapy and therefore carries a better prognosis than visceral or disseminated disease.

The best treatment outcomes of primary cutaneous mucormycosis are achieved with both complete excision and debridement of necrotic tissue and systemic antifungal therapy. Amphotericin B in conventional form (Fungizone) and liposomal form (AmBisome) and posaconazole (Noxafil)^11–12 are effective.

Paradoxically, in contrast to deferoxamine, other iron chelators such as deferiprone (Ferriprox, not available in the United States) and deferasirox (Exjade), which do not supply iron to the fungus, had been shown to be effective against Zygomycetes in in vitro and animal models. The role of iron chelators as adjunctive therapy for mucormycosis needs further investigation.⁸

Primary cutaneous mucormycosis may become a disseminated infection. Therefore, one should have a high index of suspicion. When a transplant recipient develops a cutaneous plaque or nodule, biopsy should be performed promptly. Failure to do so can increase the risk of morbidity and death.

A 39-year-old woman presented 1 month ago with left flank pain, chills, and spiking fever over the past day. She reported having an episode of acute pyelonephritis with similar manifestations 6 months previously.

Blood tests showed a leukocyte count of 12.2 × 10⁹/L (normal range 7.05–14.99 × 10⁹/L) with predominant neutrophils, C-reactive protein 6.3 mg/dL (0.0–1.0 mg/dL), blood urea nitrogen 16 mg/dL (10–25 mg/dL), and serum creatinine 1.1 mg/dL (0.70–1.40 mg/dL). Radiographic study of the kidneys, ureters, and bladder showed multiple radiopaque densities in the calyces of both kidneys (Figure 1). Computed tomography of the abdomen without contrast revealed multiple punctuated calcifications aligned concentrically in the medulla of both kidneys (Figure 2). Blood and urine cultures were positive for Escherichia coli that was sensitive to ceftriaxone (Rocephin). This antibiotic was started, and her acute pyelonephritis and bacteremia resolved.

Now, at a follow-up visit 1 month later, intravenous urography clearly shows unique linear and striated opacities and cupping of renal papillae, key features of medullary sponge kidney (Figure 3). Because medullary sponge kidney is strongly associated with kidney stones, potassium citrate is given to prevent medullary calculi formation.

KEY FEATURES

Medullary sponge kidney causes extensive cystic dilation of medullary collecting tubules.¹ It is usually an incidental finding in patients undergoing intravenous urography as part of the evaluation for infection, hematuria, or kidney stones.

The classic urographic appearance is linear striations with small brushes or “bouquets of flowers,” which represent the collection of contrast material in small papillary cysts.

Medullary sponge kidney has long been considered a congenital disorder, but the genetic defect has not yet been identified, and the pathogenesis is not yet known. It has only rarely been reported in children.²

It is usually asymptomatic, but complications may occur, including nephrocalcinosis or lithiasis, urinary tract infection, renal tubular acidosis, and impaired urine concentrating ability.

RISK OF LITHIASIS

Gambaro et al³ estimated that medullary sponge kidney is found in up to 20% of patients with urolithiasis, and that more than 70% of patients with medullary sponge kidney develop stones.

Cystic dilation of medullary collecting tubules (an anatomic abnormality) inevitably causes urinary stasis. This, combined with hypercalciuria and reduced excretion of urinary citrate and magnesium (metabolic abnormalities), contributes to lithiasis.⁴ Lithiasis in medullary sponge kidney is a well-known cause of urinary tract infection, and it tends to facilitate infective stone formation after episodes of urinary tract infection.⁵

The unique anatomic derangement of medullary sponge kidney contributes to the recurrence of pyelonephritis, in addition to the conventional risk factors—frequent sexual intercourse, avoidance of voiding because it is inconvenient, incomplete bladder emptying, ureteropelvic junction obstruction, ectopic ureter, and impaired immunity.⁶

DIAGNOSIS AND TREATMENT

Intravenous urography is the gold standard for the diagnosis of medullary sponge kidney; computed tomography and ultrasonography are generally limited in their ability to clearly show the tubular ectasia.⁷

Treatment includes antibiotics for acute pyelonephritis and thiazide diuretics and potassium citrate to prevent stone formation and renal tubular acidosis. Due to its silent course, medullary sponge kidney should be considered not only as a cause of nephrocalcinosis and nephrolithiasis, but also as a distinct entity complicating recurrent pyelonephritis.

A 39-year-old woman presented 1 month ago with left flank pain, chills, and spiking fever over the past day. She reported having an episode of acute pyelonephritis with similar manifestations 6 months previously.

Blood tests showed a leukocyte count of 12.2 × 10⁹/L (normal range 7.05–14.99 × 10⁹/L) with predominant neutrophils, C-reactive protein 6.3 mg/dL (0.0–1.0 mg/dL), blood urea nitrogen 16 mg/dL (10–25 mg/dL), and serum creatinine 1.1 mg/dL (0.70–1.40 mg/dL). Radiographic study of the kidneys, ureters, and bladder showed multiple radiopaque densities in the calyces of both kidneys (Figure 1). Computed tomography of the abdomen without contrast revealed multiple punctuated calcifications aligned concentrically in the medulla of both kidneys (Figure 2). Blood and urine cultures were positive for Escherichia coli that was sensitive to ceftriaxone (Rocephin). This antibiotic was started, and her acute pyelonephritis and bacteremia resolved.

Now, at a follow-up visit 1 month later, intravenous urography clearly shows unique linear and striated opacities and cupping of renal papillae, key features of medullary sponge kidney (Figure 3). Because medullary sponge kidney is strongly associated with kidney stones, potassium citrate is given to prevent medullary calculi formation.

KEY FEATURES

Medullary sponge kidney causes extensive cystic dilation of medullary collecting tubules.¹ It is usually an incidental finding in patients undergoing intravenous urography as part of the evaluation for infection, hematuria, or kidney stones.

The classic urographic appearance is linear striations with small brushes or “bouquets of flowers,” which represent the collection of contrast material in small papillary cysts.

Medullary sponge kidney has long been considered a congenital disorder, but the genetic defect has not yet been identified, and the pathogenesis is not yet known. It has only rarely been reported in children.²

It is usually asymptomatic, but complications may occur, including nephrocalcinosis or lithiasis, urinary tract infection, renal tubular acidosis, and impaired urine concentrating ability.

RISK OF LITHIASIS

Gambaro et al³ estimated that medullary sponge kidney is found in up to 20% of patients with urolithiasis, and that more than 70% of patients with medullary sponge kidney develop stones.

Cystic dilation of medullary collecting tubules (an anatomic abnormality) inevitably causes urinary stasis. This, combined with hypercalciuria and reduced excretion of urinary citrate and magnesium (metabolic abnormalities), contributes to lithiasis.⁴ Lithiasis in medullary sponge kidney is a well-known cause of urinary tract infection, and it tends to facilitate infective stone formation after episodes of urinary tract infection.⁵

The unique anatomic derangement of medullary sponge kidney contributes to the recurrence of pyelonephritis, in addition to the conventional risk factors—frequent sexual intercourse, avoidance of voiding because it is inconvenient, incomplete bladder emptying, ureteropelvic junction obstruction, ectopic ureter, and impaired immunity.⁶

DIAGNOSIS AND TREATMENT

Intravenous urography is the gold standard for the diagnosis of medullary sponge kidney; computed tomography and ultrasonography are generally limited in their ability to clearly show the tubular ectasia.⁷

Treatment includes antibiotics for acute pyelonephritis and thiazide diuretics and potassium citrate to prevent stone formation and renal tubular acidosis. Due to its silent course, medullary sponge kidney should be considered not only as a cause of nephrocalcinosis and nephrolithiasis, but also as a distinct entity complicating recurrent pyelonephritis.

A 39-year-old woman presented 1 month ago with left flank pain, chills, and spiking fever over the past day. She reported having an episode of acute pyelonephritis with similar manifestations 6 months previously.

Blood tests showed a leukocyte count of 12.2 × 10⁹/L (normal range 7.05–14.99 × 10⁹/L) with predominant neutrophils, C-reactive protein 6.3 mg/dL (0.0–1.0 mg/dL), blood urea nitrogen 16 mg/dL (10–25 mg/dL), and serum creatinine 1.1 mg/dL (0.70–1.40 mg/dL). Radiographic study of the kidneys, ureters, and bladder showed multiple radiopaque densities in the calyces of both kidneys (Figure 1). Computed tomography of the abdomen without contrast revealed multiple punctuated calcifications aligned concentrically in the medulla of both kidneys (Figure 2). Blood and urine cultures were positive for Escherichia coli that was sensitive to ceftriaxone (Rocephin). This antibiotic was started, and her acute pyelonephritis and bacteremia resolved.

Now, at a follow-up visit 1 month later, intravenous urography clearly shows unique linear and striated opacities and cupping of renal papillae, key features of medullary sponge kidney (Figure 3). Because medullary sponge kidney is strongly associated with kidney stones, potassium citrate is given to prevent medullary calculi formation.

KEY FEATURES

Medullary sponge kidney causes extensive cystic dilation of medullary collecting tubules.¹ It is usually an incidental finding in patients undergoing intravenous urography as part of the evaluation for infection, hematuria, or kidney stones.

The classic urographic appearance is linear striations with small brushes or “bouquets of flowers,” which represent the collection of contrast material in small papillary cysts.

Medullary sponge kidney has long been considered a congenital disorder, but the genetic defect has not yet been identified, and the pathogenesis is not yet known. It has only rarely been reported in children.²

It is usually asymptomatic, but complications may occur, including nephrocalcinosis or lithiasis, urinary tract infection, renal tubular acidosis, and impaired urine concentrating ability.

RISK OF LITHIASIS

Gambaro et al³ estimated that medullary sponge kidney is found in up to 20% of patients with urolithiasis, and that more than 70% of patients with medullary sponge kidney develop stones.

Cystic dilation of medullary collecting tubules (an anatomic abnormality) inevitably causes urinary stasis. This, combined with hypercalciuria and reduced excretion of urinary citrate and magnesium (metabolic abnormalities), contributes to lithiasis.⁴ Lithiasis in medullary sponge kidney is a well-known cause of urinary tract infection, and it tends to facilitate infective stone formation after episodes of urinary tract infection.⁵

The unique anatomic derangement of medullary sponge kidney contributes to the recurrence of pyelonephritis, in addition to the conventional risk factors—frequent sexual intercourse, avoidance of voiding because it is inconvenient, incomplete bladder emptying, ureteropelvic junction obstruction, ectopic ureter, and impaired immunity.⁶

DIAGNOSIS AND TREATMENT

Intravenous urography is the gold standard for the diagnosis of medullary sponge kidney; computed tomography and ultrasonography are generally limited in their ability to clearly show the tubular ectasia.⁷

Treatment includes antibiotics for acute pyelonephritis and thiazide diuretics and potassium citrate to prevent stone formation and renal tubular acidosis. Due to its silent course, medullary sponge kidney should be considered not only as a cause of nephrocalcinosis and nephrolithiasis, but also as a distinct entity complicating recurrent pyelonephritis.

A 60-year-old man with a history of alcoholic cirrhosis and gastrointestinal bleeding was admitted after being found unconscious. He had coffee-ground emesis and melena.

At the time of the physical examination, he was intubated and was unresponsive and hypotensive. On endoscopy, the upper half of the esophagus was normal (Figure 1), but the lower half showed signs of necrosis: the mucosa was black and covered by an exudate of the same color (Figure 2). Endoscopy also found signs of severe portal hypertensive gastropathy and multiple small ischemic ulcers in the distal duodenum. No biopsy was done because of the risk of bleeding due to coagulopathy. The patient died of hepatorenal syndrome and sepsis.

ASSOCIATED CONDITIONS

This patient had alcoholic cirrhosis and hypotension, which are significant comorbidities associated with necrotic (“black”) esophagus. Other conditions associated with black esophagus are gastric outlet obstruction, myocardial ischemia, hypersensitivity to antibiotics, certain viral infections, ketoacidosis, alcoholic hepatitis, acute renal failure, severe acid reflux, and acute pancreatitis.^1,2 The differential diagnosis includes melanosis, malignant melanoma, pseudomelanosis, acanthosis nigrans, adverse drug effects (quinidine and tetracycline), and infection (Candida and herpes).^1,3

TREATMENT AND COURSE

The treatment is mainly supportive, with intravenous fluids, proton pump inhibitors, and nothing taken orally.¹ Complications include stricture, perforation, and death.^1,3 The death rate is about 30% in these patients.³

 

 

A 60-year-old man with a history of alcoholic cirrhosis and gastrointestinal bleeding was admitted after being found unconscious. He had coffee-ground emesis and melena.

At the time of the physical examination, he was intubated and was unresponsive and hypotensive. On endoscopy, the upper half of the esophagus was normal (Figure 1), but the lower half showed signs of necrosis: the mucosa was black and covered by an exudate of the same color (Figure 2). Endoscopy also found signs of severe portal hypertensive gastropathy and multiple small ischemic ulcers in the distal duodenum. No biopsy was done because of the risk of bleeding due to coagulopathy. The patient died of hepatorenal syndrome and sepsis.

ASSOCIATED CONDITIONS

This patient had alcoholic cirrhosis and hypotension, which are significant comorbidities associated with necrotic (“black”) esophagus. Other conditions associated with black esophagus are gastric outlet obstruction, myocardial ischemia, hypersensitivity to antibiotics, certain viral infections, ketoacidosis, alcoholic hepatitis, acute renal failure, severe acid reflux, and acute pancreatitis.^1,2 The differential diagnosis includes melanosis, malignant melanoma, pseudomelanosis, acanthosis nigrans, adverse drug effects (quinidine and tetracycline), and infection (Candida and herpes).^1,3

TREATMENT AND COURSE

The treatment is mainly supportive, with intravenous fluids, proton pump inhibitors, and nothing taken orally.¹ Complications include stricture, perforation, and death.^1,3 The death rate is about 30% in these patients.³

 

 

A 60-year-old man with a history of alcoholic cirrhosis and gastrointestinal bleeding was admitted after being found unconscious. He had coffee-ground emesis and melena.

At the time of the physical examination, he was intubated and was unresponsive and hypotensive. On endoscopy, the upper half of the esophagus was normal (Figure 1), but the lower half showed signs of necrosis: the mucosa was black and covered by an exudate of the same color (Figure 2). Endoscopy also found signs of severe portal hypertensive gastropathy and multiple small ischemic ulcers in the distal duodenum. No biopsy was done because of the risk of bleeding due to coagulopathy. The patient died of hepatorenal syndrome and sepsis.

ASSOCIATED CONDITIONS

This patient had alcoholic cirrhosis and hypotension, which are significant comorbidities associated with necrotic (“black”) esophagus. Other conditions associated with black esophagus are gastric outlet obstruction, myocardial ischemia, hypersensitivity to antibiotics, certain viral infections, ketoacidosis, alcoholic hepatitis, acute renal failure, severe acid reflux, and acute pancreatitis.^1,2 The differential diagnosis includes melanosis, malignant melanoma, pseudomelanosis, acanthosis nigrans, adverse drug effects (quinidine and tetracycline), and infection (Candida and herpes).^1,3

TREATMENT AND COURSE

The treatment is mainly supportive, with intravenous fluids, proton pump inhibitors, and nothing taken orally.¹ Complications include stricture, perforation, and death.^1,3 The death rate is about 30% in these patients.³

 

 

A 57-year-old woman says that for the past 30 years she has been aware of thickening, reduction in the growth rate, and yellow discoloration of the nail beds of her fingers and toes. Nail clippings were cultured about 10 years ago, but no fungus was isolated. About 7 years after she first noticed the nail changes, she developed pitting edema of the ankles without evidence of cardiac failure, and she was put on a diuretic.

A chest radiograph taken 8 years ago during a health examination was normal. However, 1 month before admission to our department, she began experiencing exertional dyspnea, with productive cough but no fever.

She has never traveled abroad, has no history of hypertension or ischemic cardiomyopathy, has never undergone surgery, and has no history of tuberculosis.

EXAMINATION AND TESTING

On examination, the patient has thickened yellowish nails on all fingers and toes (Figure 1). Radiography and computed tomography (Figure 2) show a unilateral pleural fluid accumulation but no obvious inflammatory changes or tumor.

Thoracocentesis reveals an exudative pleural fluid with a high protein concentration, a normal lactate dehydrogenase concentration, and an elevated lymphocyte count.

Q: Which of the following is the most likely diagnosis?

• Cardiac failure
• Yellow nail syndrome
• Infection
• Neoplastic disease

A: The correct diagnosis is yellow nail syndrome, a rare disorder characterized by yellow nails, lymphedema, and chronic respiratory manifestations. However, patients rarely present with all three parts of the triad, and fewer than half of patients present with pleural effusions.

The respiratory manifestations of yellow nail syndrome are diverse and include pleural effusion, bronchiectasis, rhinosinusitis, chronic cough, and recurrent lung infections. Furthermore, this syndrome is in the differential diagnosis of chronic pleural effusions lasting more than 1 year, and also of bronchiectasis and rhinosinusitis.

The pathophysiology of yellow nail syndrome remains unclear, but various anatomic or functional lymphatic drainage abnormalities have been proposed as the underlying cause.

Therapy includes bronchopulmonary hygiene (eg, postural drainage); inhaled steroids and antibiotics to control exacerbations of symptoms; serial thoracocentesis or pleurodesis to control pleural effusions; and lymphatic drainage and diuretic drugs for lymphedema. Some experts propose vitamin E for the treatment of yellow nails, but yellow nails often improve spontaneously.

CASE CONCLUDED

In this case, the diagnosis of yellow nail syndrome was based on the presence of its three major features. She had no history of hypertension or ischemic cardiomyopathy, and no echocardiographic signs of cardiac failure. She had no signs of infection or malignancy and had never taken antirheumatic drugs such as d-penicillamine (Cuprimine, Depen), which can cause pleural effusion, and nothing in her history or presentation suggested an immunosuppressed state.

Her treatment involved thoracocentesis to reduce the pleural effusion, correction of her nutritional status, a low-salt diet, vitamin E supplementation, and diuretics. At discharge, her pleural effusion and lymphedema were reduced, and her dyspnea had resolved.

A 57-year-old woman says that for the past 30 years she has been aware of thickening, reduction in the growth rate, and yellow discoloration of the nail beds of her fingers and toes. Nail clippings were cultured about 10 years ago, but no fungus was isolated. About 7 years after she first noticed the nail changes, she developed pitting edema of the ankles without evidence of cardiac failure, and she was put on a diuretic.

A chest radiograph taken 8 years ago during a health examination was normal. However, 1 month before admission to our department, she began experiencing exertional dyspnea, with productive cough but no fever.

She has never traveled abroad, has no history of hypertension or ischemic cardiomyopathy, has never undergone surgery, and has no history of tuberculosis.

EXAMINATION AND TESTING

On examination, the patient has thickened yellowish nails on all fingers and toes (Figure 1). Radiography and computed tomography (Figure 2) show a unilateral pleural fluid accumulation but no obvious inflammatory changes or tumor.

Thoracocentesis reveals an exudative pleural fluid with a high protein concentration, a normal lactate dehydrogenase concentration, and an elevated lymphocyte count.

Q: Which of the following is the most likely diagnosis?

• Cardiac failure
• Yellow nail syndrome
• Infection
• Neoplastic disease

A: The correct diagnosis is yellow nail syndrome, a rare disorder characterized by yellow nails, lymphedema, and chronic respiratory manifestations. However, patients rarely present with all three parts of the triad, and fewer than half of patients present with pleural effusions.

The respiratory manifestations of yellow nail syndrome are diverse and include pleural effusion, bronchiectasis, rhinosinusitis, chronic cough, and recurrent lung infections. Furthermore, this syndrome is in the differential diagnosis of chronic pleural effusions lasting more than 1 year, and also of bronchiectasis and rhinosinusitis.

The pathophysiology of yellow nail syndrome remains unclear, but various anatomic or functional lymphatic drainage abnormalities have been proposed as the underlying cause.

Therapy includes bronchopulmonary hygiene (eg, postural drainage); inhaled steroids and antibiotics to control exacerbations of symptoms; serial thoracocentesis or pleurodesis to control pleural effusions; and lymphatic drainage and diuretic drugs for lymphedema. Some experts propose vitamin E for the treatment of yellow nails, but yellow nails often improve spontaneously.

CASE CONCLUDED

In this case, the diagnosis of yellow nail syndrome was based on the presence of its three major features. She had no history of hypertension or ischemic cardiomyopathy, and no echocardiographic signs of cardiac failure. She had no signs of infection or malignancy and had never taken antirheumatic drugs such as d-penicillamine (Cuprimine, Depen), which can cause pleural effusion, and nothing in her history or presentation suggested an immunosuppressed state.

Her treatment involved thoracocentesis to reduce the pleural effusion, correction of her nutritional status, a low-salt diet, vitamin E supplementation, and diuretics. At discharge, her pleural effusion and lymphedema were reduced, and her dyspnea had resolved.

A 57-year-old woman says that for the past 30 years she has been aware of thickening, reduction in the growth rate, and yellow discoloration of the nail beds of her fingers and toes. Nail clippings were cultured about 10 years ago, but no fungus was isolated. About 7 years after she first noticed the nail changes, she developed pitting edema of the ankles without evidence of cardiac failure, and she was put on a diuretic.

A chest radiograph taken 8 years ago during a health examination was normal. However, 1 month before admission to our department, she began experiencing exertional dyspnea, with productive cough but no fever.

She has never traveled abroad, has no history of hypertension or ischemic cardiomyopathy, has never undergone surgery, and has no history of tuberculosis.

EXAMINATION AND TESTING

On examination, the patient has thickened yellowish nails on all fingers and toes (Figure 1). Radiography and computed tomography (Figure 2) show a unilateral pleural fluid accumulation but no obvious inflammatory changes or tumor.

Thoracocentesis reveals an exudative pleural fluid with a high protein concentration, a normal lactate dehydrogenase concentration, and an elevated lymphocyte count.

Q: Which of the following is the most likely diagnosis?

• Cardiac failure
• Yellow nail syndrome
• Infection
• Neoplastic disease

A: The correct diagnosis is yellow nail syndrome, a rare disorder characterized by yellow nails, lymphedema, and chronic respiratory manifestations. However, patients rarely present with all three parts of the triad, and fewer than half of patients present with pleural effusions.

The respiratory manifestations of yellow nail syndrome are diverse and include pleural effusion, bronchiectasis, rhinosinusitis, chronic cough, and recurrent lung infections. Furthermore, this syndrome is in the differential diagnosis of chronic pleural effusions lasting more than 1 year, and also of bronchiectasis and rhinosinusitis.

The pathophysiology of yellow nail syndrome remains unclear, but various anatomic or functional lymphatic drainage abnormalities have been proposed as the underlying cause.

Therapy includes bronchopulmonary hygiene (eg, postural drainage); inhaled steroids and antibiotics to control exacerbations of symptoms; serial thoracocentesis or pleurodesis to control pleural effusions; and lymphatic drainage and diuretic drugs for lymphedema. Some experts propose vitamin E for the treatment of yellow nails, but yellow nails often improve spontaneously.

CASE CONCLUDED

In this case, the diagnosis of yellow nail syndrome was based on the presence of its three major features. She had no history of hypertension or ischemic cardiomyopathy, and no echocardiographic signs of cardiac failure. She had no signs of infection or malignancy and had never taken antirheumatic drugs such as d-penicillamine (Cuprimine, Depen), which can cause pleural effusion, and nothing in her history or presentation suggested an immunosuppressed state.

Her treatment involved thoracocentesis to reduce the pleural effusion, correction of her nutritional status, a low-salt diet, vitamin E supplementation, and diuretics. At discharge, her pleural effusion and lymphedema were reduced, and her dyspnea had resolved.