“Invasive Pulmonary Aspergillosis: An Old Kid On The Block”: Report Of Three Cases And Review Of Literature
J Orsini, C McCalla, T Lenox
hivaids, immunosupression, invasive pulmonary aspergillosis
J Orsini, C McCalla, T Lenox. “Invasive Pulmonary Aspergillosis: An Old Kid On The Block”: Report Of Three Cases And Review Of Literature. The Internet Journal of Infectious Diseases. 2006 Volume 6 Number 1.
Since the start of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980's, respiratory diseases have been an important cause of morbidity and mortality among these patients. Majority of the human immunodeficiency virus (HIV) infected patients encounters a pulmonary complication during the course of their illness.
Invasive pulmonary aspergillosis is the most common invasive fungal infection worldwide, and a major cause of mortality among immunosupressed patients despite adequate therapy. The diagnosis, although difficult to achieved, should be consider in immunosuppressed patients with fever no responding to antibiotic therapy, and those with typical findings on thoracic imaging. Whenever possible, diagnosis should be confirmed by histopathologic examination. Incidence has risen due to more intensive anticancer chemotherapy, organ transplantation, aggressive surgical interventions and prolonged survival among HIV-infected patients due to highly active antiretroviral therapy.
We report 3 cases of invasive pulmonary aspergillosis in severely immunocompromised hosts, in whom the diagnosis was made by autopsy.
A 38-year-old hispanic male had a medical history significant for HIV/AIDS, Kaposi's sarcoma of the skin and substance abuse. He was admitted to the hospital with 3 weeks history of cough, tachypnea, pleuritic pain, fever and weight loss.
Vital signs on admission were: blood pressure of 100/50 mmHg, heart rate of 92 beats/min, respiratory rate of 22 breaths/min, and temperature of 101°F. Physical examination showed a cachectic male, in mild respiratory distress with bilateral crackles on auscultation. He had several dark pigmented skin lesions in the trunk and upper extremities.
The complete blood count showed a white blood cells of 1,320/mm3, a hemoglobin level of 7.5 g/dl, and a platelet count of 164,000/mm3. Relevant serum chemistry included a sodium of 150 mEq/L, a creatinine level of 0.5 mg/dl, and a lactate dehydrogenase enzyme level of 301 units/L. His CD4 count was 14/cumm. Serum cryptococcal antigen was negative, and urine antigen for
Intravenous vancomycin (1 g Q12h), cefepime (2 g Q8h) and pentamidine (4 mg/kg Q24h) were initiated empirically. After 48 hours developed respiratory failure and was placed on mechanical ventilation. Intravenous voriconazole (4 mg/kg Q12h) was added. His hospital course was complicated with acute renal failure, septic shock and, ultimately, pulseless electrical activity and cardiac arrest.
All cultures done during hospitalization were negative. Autopsy showed angio-invasive aspergillosis of the lungs as the main cause of death. (FIGURE 1) Also, Kaposi's sarcoma of the lungs and skin was found.
An african-american female was admitted for generalized papular-vesicular rash, lethargy, cough and weight loss for 3 weeks. She was 48-year-old with unknown past medical history at the time of admission, but her husband died from acquired immunodeficiency syndrome (AIDS).
Vital signs were: blood pressure of 90/67 mmHg, heart rate of 126 beats/min, and respiratory rate of 22 breaths/min. She was afebrile. Remarkable findings on physical examination included vesicular lesions with excoriations in the face, anterior thoracic and abdominal walls, oropharyngeal thrush, and bilateral rales on auscultation. She was alert but confused.
Complete blood count showed a white blood cells of 15,500/mm3, a hemoglobin level of 12 mg/dl, and a platelet count of 232,000/mm3. Relevant chemistry results included a sodium level of 125 mEq/L, bicarbonate level of 15 mEq/L, and a creatinine level of 2.5 mg/dl. Alkaline phosphatase level was 346 units/L. Arterial blood gas results were compatible with hypoxemic respiratory failure. Lactic acid level was 4.7 mg/dl. Chest radiograph showed multiple diffuse densities. (FIGURE 2)
Intravenous vancomycin (500 mg Q24h), cefepime (1 g Q24h), acyclovir (350 mg Q24h), fluconazole (200 mg Q24h), azithromycin (500 mg Q24h) and trimethoprim/sulfametoxazole (15 mg/kg Q24h) were initiated empirically along with vasopressors and steroids.
Hospital course was complicated with respiratory failure requiring mechanical ventilation and multi-organ dysfunction syndrome. On day 6th of admission developed bradycardia and cardiac arrest.
Post-mortem histopathology examination showed angio-invasive pulmonary aspergillosis with hemorrhagic infarction of the lungs as the main cause of death.
A 41-year-old african-american female wad admitted for shortness of breath. On arrival to emergency room was intubated and placed on mechanical ventilation due to severe respiratory distress. Her past medical history was significant for HIV/AIDS, diabetes mellitus and gastro-esophageal reflux disease.
Vital signs on admission were: blood pressure of 100/60 mmHg, heart rate of 136 beats/min, respiratory rate of 26 breaths/min, and temperature of 99?F. She had bilateral rales on lung auscultation. Complete blood count showed white blood cells of 6,900/mm3, a hemoglobin level of 10.5 mg/dl, and a platelet count of 405,000/mm3. Serum sodium level was 130 mEq/L, and a creatinine level was 1.9 mg/dl. Aspartate aminotransferase and alanine aminotransferase levels of 90 and 96 units/L respectively, lactate dehydrogenase enzyme level of 236 units/L, and alkaline phosphatase level of 555 units/L. CD4 count was 55/cumm.
Intravenous vancomycin (1 g Q24h), piperacilin/tazobactam (3.375 g Q8h), pentamidine (4 mg/kg Q24h) and prednisone were empirically initiated. During hospitalization she developed cardiac arrest and anoxic encephalopathy. Blood cultures were positive for
Plain chest radiograph showed bilateral increased interstitial markings with a left upper lobe infiltrate. Chest computed tomography showed extensive bilateral infiltrates with multiple non-uniform cystic spaces and minimal bronchial dilatation. (FIGURES 6-7) Amphotericin B (50 mg Q24h), isoniazide, rifabutin, ethambutol, pyrazinamide and clarithromycin were added to the therapy. Patient expired after 1 week. Autopsy demonstrated bilateral pulmonary aspergillosis with tracheal involvement and
Antifungal defenses in humans are based on normal mucosa barriers, macrophages and neutrophil function as well as tumor necrosis factor alpha and macrophage inflammatory protein (MIP-1 alpha), that are reduced in neutropenic hosts (17).
There are different types of infection caused by
Different classification criteria have been proposed for the diagnosis of aspergillosis:
Several radiographic patterns could be found in invasive pulmonary aspergillosis. The commonest radiologic finding is a thick-walled cavity with or without an intracavitary mass, probably due to hemorraghic infarction resulting from angioinvasion (38, 39). HIV-infected patients with lung cavities and prolonged hospitalizations are at increased risk for invasive pulmonary aspergillosis (40). The appearance of a hemorrhagic pulmonary nodule or “halo sign” is typical but not patognomonic of invasive pulmonary aspergillosis, since it can be present in other pulmonary disorders such as alveolar hemorrhage, bronchiolitis obliterans organizing pneumonia, viral infections, Kaposi's sarcoma, Wegener's granulomatosis and angiosarcoma. “Halo sign” is also found with other fungi infections such as
Definite diagnosis of invasive aspergillosis is established by tissue examination. The histopathology will show a tissue reaction with an acute supurative inflammation, areas of ischemic necrosis, and the presence of septate hyphae that branches at 45? angles. The septated hyphae of
The most commonly used serologic test to diagnose invasive pulmonary aspergillosis is based on the detection of antigens, especially galactomannan (GM) antigen, a polysaccharide component of the fungal wall released into surrounding tissue during hyphal growth. It has a sensitivity of more than 90% and specificity of 95% using a sandwich enzyme-linked immunosorbent assay (57). There is an improved sensitivity of the sandwich ELISA assay compared with the latex-agglutination assay, but up to 14% of false-positive results has been reported (58). Sensitivity of antigen testing is dependent of the extension and severity of the disease, and increased when a low index cutoff value of <1.0 is used to define positivity (59). In patients receiving mold-active antifungal therapy there is a decrease sensitivity of the serum assay, impairing the ability of the test to provide an early indicator of breakthrough infection (59). Cross-reactivity has been reported against
Another serologic test useful in the diagnosis is the detection of
Early diagnosis and appropriate therapy are imperative in patients with invasive pulmonary aspergillosis. An aggressive diagnostic approach in patients at risk and prompt institution of antifungal therapy is essential for survival (70). Initial therapy is very important and intravenous treatment may be preferred in acutely ill patients (2). Amphotericin B or lipid-based formulations in patients with altered renal function has been the standard of treatment for patients with invasive aspergillosis (2). Better outcomes have been seen when voriconazole is selected as initial treatment (71). Voriconazole is recommended as initial therapy because of better clinical responses and improved survival when compared with other azoles, amphotericin B formulations and echinocandins. Also, voriconazole have better tolerance and less side effects than the conventional/standard therapy with amphotericin B (72). Great response is obtained when voriconazole plasma levels are more than 250 ng/µl. Most of the adverse effects such as visual disturbances, confusion, skin rash and abnormal liver function test are associated with plasma levels of more than 6000 ng/µl (73).
For salvage therapy, amphotericin B formulations should not be recommended when amphotericin B formulations were used as initial therapy (74). Caspofungin has been used effectively as an alternative for salvage treatment of invasive pulmonary aspergillosis (75). The underlying medical condition and previous treatment exposure substantially contributes to the clinical outcome for antifungal therapy. Patients with persistent neutropenia and underlying malignancy have the worst prognosis (76).
Although not clear clinical data is available, some physicians are using combination antifungal therapy because of the persistently high mortality rate associated with aspergillosis, even among patients treated with voriconazole for salvage therapy. In some studies, the combination of voriconazole and caspofungin was associated with improved 3-month survival rate compared with voriconazole as a single therapy in patients receiving salvage therapy to treat aspergillosis (77). Other possible combinations include azoles or amphotericin B with echinocandins such as caspofungin, micafungin and nikkomycin Z, the latter only active against
Additive therapy to antifungal treatment include cytokines, such as granulocyte-macrophage colony stimulating factor, interferon-gamma and granulocyte transfusions, but these are not recommended for routine therapy (2, 82, 83).
Surgical treatment is an option in cases of localized disease that is unresponsive to antifungal therapy (52). Surgery is usually done to prevent severe hemoptysis, especially after the neutropenia had resolved, although there is not contraindications for thoracic surgery in these patients (31, 84). Aggressive surgical management improves the prognosis of invasive pulmonary aspergillosis in some patients (85). Cases of recurrent pulmonary and pleural aspergillosis have been reported after surgery (86).
Mortality remains high in patients with invasive aspergillosis despite appropriate treatment. The overall case-fatality rate is about 60%, and is higher among bone marrow transplant recipients and for patients with central nervous system involvement or disseminated aspergillosis (27). Patients with HIV-infection have a case-fatality rate of about 85%, probably because the underlying immunosuppressive condition is progressive, irreversible, and because these patients are more likely to have diffuse invasive pulmonary aspergillosis (27, 87). Autopsy findings in patients with AIDS revealed that mortality from fungal infections has been increasing or, at least, remains unchanged (88, 89). Kaposi's sarcoma and
Invasive pulmonary aspergillosis is an important and commonly fatal complication of advanced HIV infection. Although invasive pulmonary aspergillosis remains a life-threatening complication among immunocompromissed patients, with a persistently high case-fatality rate, aggressive diagnostic evaluation and initiation of treatment are essential to improve its prognosis.
Clinically, the onset of invasive pulmonary aspergillosis is highly variable and plain chest radiographs are nonspecific in early stages of the disease. Therefore, clinicians should suspect the diagnosis in the setting of immunosuppressed patients with persistent fever, prolonged neutropenia, and those with persistent pulmonary infiltrates. There has been a substantial increased in the number of cases documented at autopsy. Causes of death established postmortem have been frequently shown to differ from those suspected by clinicians. However, invasive aspergillosis is a devastating infection, and the fact that all our cases were diagnosed post-mortem confirms the perception of the emergence of invasive aspergillosis in AIDS patients.
Jose Orsini, M.D. New York Medical College Westchester Medical Center/Metropolitan Hospital Center Division of Infectious Diseases Munger Pavilion, Room 245 Valhalla, NY 10595 Telef. #: 914-493-8865 Fax #: 914-594-4673 E-mail: firstname.lastname@example.org