Pulmonary Invasive Aspergillosis Presenting as Leucocytosis in a Patient on Immunosuppression after Renal Transplantation

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Abstract

Leucocytosis without any clinical symptoms is a diagnostic dilemma more so in an immunocompromised host. We describe the occurrence of invasive aspergillosis in a 63 year old male on immunosuppressive therapy after renal transplantation.

Pulmonary involvement with invasive aspergillosis presents with fever, cough and chest pain. The clinical presentation of this patient was leucocytosis without any pertinent clinical symptoms. Chest X-Ray and CT scan are suggestive although not diagnostic. The diagnosis is made by obtaining the tissue and isolation of aspergillus species on culture. Many antifungal therapies are available, although, Voriconazole is recommended as the initial drug of choice. Invasive aspergillosis should be in the differential diagnosis of immunosuppresed patients with signs and/or symptoms of unexplained infective process.

The Case

A 63-year-old Hispanic man presented to the renal clinic on 1/22/07 for his follow up visit. On routine blood work, the patient was found to have increased white blood cell count of 17,000/ cmm with neutrophil count of 91% and bands of 48%. The patient did not have any clinical symptoms except for dry cough for a few days and intermittent diarrhea 3 days ago. His past medical history included renal transplantation for IgM nephropathy in September 2006, hyperlipidemia on atorvastatin, and he was PPD positive treated with 9 months of INH in 1990. He was recently discharged from the hospital after treatment for community acquired pneumonia. His medications included tacrolimus, prednisone, mycophenolate, valganciclovir, bactrim, atorvastatin. The patient had completed the course of augmentin and azithromycin a day before follow up in the renal clinic.

On physical examination, the patient was comfortable and was not in distress. He was afebrile with a regular pulse rate of 79 beats per minute, blood pressure of 146/89 mm Hg, and respiratory rate of 19 per minute. The Chest examination indicated decreased breath sounds in the right lower lobe on auscultation, associated with increased tactile fremitus and resonance on the right side.

The initial workup included a complete blood cell count (CBC), basic metabolic panel, blood culture, fungal culture, mycobacterium culture and HIV testing. Sputum was tested for acid fast bacilli and Pneumocystis . Stool was tested for clostridium difficile. The patient was placed on contact and airborne isolation pending results.. Meanwhile infectious disease and renal teams were consulted.

01/26/07 01/25/07 01/24/07 01/22/07 01/22/07 UNITS REFERENCE
WBC 14 H 14.7 H 17.5 H 16.7 H 17.7 H K/cmm 4.8-10.8
HGB 11.3 L 11.8 L 12.4 L 10.7 L 11.0 L g/dL 14-18
PLT 246 328 358 336 353 K/cmm 130-400
NEUT% 93.6 H 92.7 H 94.9 H 91.7 H 90.5 H % 40-74
BANDS 16 H 48 H 20 H % 0-9

Basic metabolic panel, hepatic panel, coagulation profile were within normal limits. Chest radiograph was suggestive of areas of cavitation within right middle lobe infiltrate consistent with areas of lung abscess which was confirmed by CT of the thorax (Figure 1,2).

Figure 1. Chest X-Ray showing areas of cavitation seen within right middle lobe infiltrate.
Figure 1. Chest X-Ray showing areas of cavitation seen within right middle lobe infiltrate.
Figure 2. Chest CT showing multiple thickwalled cavitary pulmonary nodules.
Figure 2. Chest CT showing multiple thickwalled cavitary pulmonary nodules.

The patient was found to be sputum AFB-PCP negative, C.diff.negative. Bronchoscopy with transbronchial biopsy of the lower lobe of the right lung demonstrated septate fungal hyphae suggesting Aspergillus in completely necrotic tissue fragment stained with GMS (Figure 3). Mycology culture of the bronchial brushing cytologic material was positive for Aspergillus fumigatus. Patient was started on Voriconazole 200 mg every 12 hourly for 2 weeks with follow up in pulmonary clinic after 2 weeks.

Figure 3. Sediment from bronchoalveolar lavage was centrifuged and processed as a cell block; sections were stained with H&E and with PAS-diastase. Septate fungal hyphae with dichotomous branching, characteristic of Aspergillus were found.
Figure 3. Sediment from bronchoalveolar lavage was centrifuged and processed as a cell block; sections were stained with H&E and with PAS-diastase. Septate fungal hyphae with dichotomous branching, characteristic of Aspergillus were found.

Discussion

Invasive aspergillosis first described in 1953, is an acute progressive infection and the clinical features depend upon the anatomic site involved. 1  Common features of pulmonary involvement include fever not responding to broad spectrum antibiotics, pleuritic chest pain, cough, and hemoptysis. 2  Presentation as asymptomatic leucocytosis is uncommon and not described in the literature. Our patient did not have fever and only had partially improved dry cough at the time of presentation. The chest X-Ray in these patients shows nodular lesions or patchy infiltrates. Chest X-Ray may be normal in 10% cases with a normal CT scan in 3%. 3

There are approximately 200 species of aspergillus, however, only few are known to be of pathogenic concern for humans, which includes A. flavus, A. fumigatus, A. niger as the most commonly found species in humans. 4  The frequent risk factors for invasive aspergillosis include bone marrow transplantation (32%), hematologic malignancy (29), solid organ transplantation (9%), and AIDS (8%). 3  Patients with solid organ transplantation are susceptible as they are on immunosuppression regimen. Of the various immunosuppressive agents, corticosteroids are most notorious and make patients vulnerable for infection with aspergillus. In 2% of subjects, no underlying risk factor could be identified. 3

The adhesion of Aspergillus conidia to host cell and/or to the extracellular matrix is thought as the development of Aspergillus infection. 5  The innate and adaptive cellular responses to Aspergillus infection are upregulated by secretion of cytokines, chemokines and an Aspergillus-specific, acute-phase reactant (pentraxin) by the macrophages. 6 7  The subacute progression of invasive aspergillosis may be caused by global dysregulation of lymphopenia of the host adaptive TH1-TH2 polarization. 8 9

The diagnosis of pulmonary invasive aspergillosis is made based on tissue histopathology suggestive of septate hyphae and a positive culture from tissue obtained by transbronchial, open lung, or percutaneous needle biopsy. 10  The differential diagnosis in this patient with renal transplant on immunosuppresants includes infections with nocardia, sporothrix, actinomyces. 11  High-resolution Chest CT is a useful tool for early diagnosis and leads to further diagnostic tests like bronchoscopy and open lung biopsy. 12  Typical chest CT findings such as a halo sign, an early radiologic sign that appears as a zone of low attenuation due to hemorrhage surrounding the pulmonary nodule and air crescent sign, is a crescent shaped lucency in the region of original nodule secondary to necrosis – are neither sensitive nor pathognomic for diagnosis as other infections like nocardiosis, zygomycoses have similar findings. 13 14  Bronchioalveolar lavage is helpful in diagnosis is diffuse lung involvement with a high specificity of 97% but the sensitivity is reported to be 30-50%. 15

Systemic antifungals remain the mainstay of treatment. The outcome of therapy is dependent on early diagnosis, absence of dissemination, tapering of immunosuppression drugs, and initiation of antifungal therapy. 16  A recent study investigating the invitro pharmacodynamics of of amphotericin B, itraconazole, and voriconazole against Aspergillus, Fusarium, and Scedosporium species to directly visualize hyphal damage was suggestive of hyphal damage more frequently with voriconazole and amphotericin B versus itraconazole. 17  Amphotericin B with newer lipid-based preparations is useful in patients with high risk for renal toxicity. The usual dose is 0.6 to 1.2mg/kg/d. Of the anti-fungal preparations available, Voriconazole is recommended as the first line drug for treating invasive aspergillosis. 18  It is given as intra-venous preparation initially as 6 mg/kg/d followed by 200 mg twice a day orally once the patient is stable. In one randomized unblended study, Voriconazole was better compared to amphotericin B at week 12 in terms of successful outcome and survival (53 % vs. 32%; CI 10-33 and 71 % vs. 58%; CI- 0.4- 0.9). 19  The total duration of treatment is unknown, however, radiological improvement usually starts 3-4 weeks after starting therapy. Drug is continued for 2 weeks after clinical and radiological recovery. 20  Patients who do not respond to Voriconazole are started on liposomal amphotericin B in addition to Voriconazole. The drug is safe except transient visual disturbances in 45% cases. Liver function tests are routinely monitored for patients on Voriconazole. 21

Avoiding hospitalization of patients in construction zones, and use of high efficiency laminar air flow have been shown to decrease the rate of invasive aspergillosis in some studies. 22

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