Acute Lymphoblastic Leukemia, Invasive Aspergillus Fungal Pneumonia and Complications: A Pandora’s Box

Introduction

Leukemia is a hematological malignancy characterized by over production of immature white blood cells. It is classified as myeloid or lymphoblastic variety. The symptoms often masquerade as a common illness by manifesting as fever, weight loss and fatigue.¹

Organomegaly affecting the liver and spleen, and lymphadenopathy are observed. The patients are at an increased risk for spontaneous bleeding and infections. Morbidity and mortality can be the result of disease or can result from chemotherapy and its complications.^1,2 The case report discussed below provides a glimpse into the complications commonly encountered due to fungal pathogens such as Aspergillus. Radiology plays an important role in the early detection and timely institution of treatment, thereby reducing complications.

Case Report

A nine year old girl, with a history of B cell Acute lymphoblastic leukemia (ALL), post-chemotherapy presented with fever, cough, vomiting and loose stools. On examination, the patient was febrile (100.6^o F) with mild tachycardia (100 b/m). A respiratory rate of 20/m and SpO2 of 98% were recorded which were within the normal range. The Glasgow Coma Scale (GCS) was 15/15.

Blood investigations revealed Hb 9.8 gm/dL, WBC 190 cells/dL, absolute neutrophil count (ANC) 19/mL, Platelets 2000/m, C-reactive protein (CRP) 93 mg/mL, Procalcitonin (PCT) 9.36 ng/mL. The liver and renal biochemistry was within normal range. Patient was diagnosed as febrile neutropenia. 

Patient’s chest x-ray revealed nodular opacities (Figure 1) and therefore high-resolution computed tomography (HRCT) evaluation was advised. On HRCT, multiple nodular parenchymal lesions were observed with ground glass halo (Figure 2). Diagnosis of fungal pneumonia was made in view of presence of nodules revealing the ‘halo sign’. The galactomannan test subsequently conducted was positive.

Patient was treated with antifungal medication (Amphotericin B/Voriconazole) and antibacterial drugs such as injection Meropenem and Amikacin.

Patient was monitored in PICU. Patient continued to have fever spikes and third space fluid collections. Patient developed large left sided pleural effusion (Figure 3) with hypoalbuminaemia (2.2 mg/dL). Patient biofire (Respiratory pathogen panel test) revealed parainfluenza type 3 infection. On serial follow-up, patient’s ANC improved with marrow showing changes of remission.

Patient had episodes of diarrhea and pain in the abdomen. Patient later developed swelling in the hands and in the post-auricular region. The post-auricular swelling was extremely tender. Possibility of abscess formation was considered and ultrasound was carried out.

Ultrasound revealed post-auricular swelling to be pseudo-aneurysm from the post-auricular branch of the external carotid artery (Figure 4). This was further confirmed with CT angiography (Figure 5).

In addition, there was development of retroperitoneal abscess (Figure 6) and intramuscular abscess in the hand. These were drained under imaging guidance. The cultures grew Methicillin-resistant Staphylococcus aureus (MRSA). The pseudo-aneurysm was embolized with digital subtraction angiography. Patients’ condition subsequently improved with reduction in fever spikes. Patient was monitored in the ward with IV antifungals and antibiotics and was subsequently discharged.

Discussion

Acute lymphoblastic leukemia is a malignancy of B/T lymphocytes with uncontrolled proliferation of the immature lymphocyte population. A progressive replacement of the bone marrow and other lymphoid organs by the abnormal cells is observed. The common symptoms include fatigue, bruising, spontaneous bleeding and infections.¹

Patients of leukemia are at an increased risk for infections, both as a result of disease itself and due to the complications associated with chemotherapy. Neutropenia is the major determinant of development of infections.²

Early neutropenia predisposes the patient to bacterial infections. Prolonged neutropenia for more than three weeks increases the risk of fungal infections and pneumonia. Clinical signs are misleading in leukemia as fever could be the result of disease itself or be related to the treatment.

Aspergillus is a fairly ubiquitous pathogen; it is harmless if the host immunity is intact. It is usually encountered as aspergilloma in the tubercular cavity (Figure 7). In patients with long standing asthma, it manifests as Allergic Bronchopulmonary Aspergillosis (ABPA). This is noted as bronchiectatic dilation and cystic changes (Figure 8). Its severe spectrum includes invasive aspergillosis.

Fungal pneumonia is a serious cause of morbidity and mortality in leukemia. Involvement could be through the blood stream, visceral organs or sinuses. Invasive candidiasis is most common example of the blood stream type, whereas lungs and sinuses are the most common organs involved in invasive aspergillosis.³

Aspergillus can present as angio-invasive type or airway disease type. The angio-invasive pattern is commoner. The angio-invasive type classically manifests on the HRCT as a nodule surrounded by ground glass halo. The nodular consolidation seen in pathology corresponds to the fungal colonization and the ground glass manifestation is due to hemorrhagic areas of infarction.

Cavitations and air crescents are noted at later stages (Figure 9). The air crescent sign corresponds with improvement in neutropenia. HRCT thus helps in rapid diagnosis of the invasive fungal pneumonia much before laboratory tests become positive. The airway disease manifests radiologically as centrilobular nodulation and peribronchial consolidation.⁴

A multi-institutional study evaluated the clinical significance of the ground glass halo sign in invasive pulmonary aspergillosis. Of 235 cases reviewed, 61% cases manifested with ground glass halo sign on HRCT. Consolidation, infarct-shaped nodules, air crescent sign and cavitation were the other features observed. Improved outcomes and survival benefits were noted in those in whom antifungal treatment was instituted on the basis of Halo sign.⁵

Other pulmonary manifestations of leukemia are more related to the primary disease itself due to an uncontrolled increase in cell population. These include leukemic pulmonary infiltration, leukostasis and acute leukemic cell pneumopathy (Figure 10). The leukemic pulmonary infiltration presents as an interstitial nodular thickening. Leukostasis results in plugging of small vessels with leukemic cells. This can manifest radiologically as an acute interstitial edema. Acute leukemic cell pneumopathy is a condition that manifests radiologically and clinically as acute respiratory distress syndrome (ARDS) due to tumoral cell lysis following initiation of therapy.⁶

Vascular aneurysms and hemorrhage are other causes of unexplained morbidity and mortality in leukemic patients (Figure 11). Multiple case reports can be cited in literature on intracranial, visceral and peripheral aneurysms.⁷

The exact pathogenesis remains obscure, but fungal infections and vascular infiltration by myeloid cells are the probable suspects. In our case, the aneurysm developed after pulmonary fungal pneumonia with high probability of fungal etiology for the same. The abscess although grew MRSA which can be a secondary bacterial infection in the background of a leukemic immune-compromised state.

The aneurysms of the carotid artery are otherwise rare in non-hematological conditions. Those of the external carotid artery are extremely unusual. The various possible causes cited in the literature include mycotic aneurysm, trauma, fibromuscular dysplasia, dissection, connective tissue disorders, radiation and congenital disorders.⁸ Vascular aneurysm and hemorrhagic complications are seen and reported far more commonly in hematological malignancies.

Infectious diseases constitute a major cause of morbidity and mortality in leukemic patients. Neutropenia happens to be a predominant predisposing factor. The initial infections are bacterial in nature. If neutropenia persists, growth of fungal pathogens can lead to multitude of other complications such as aneurysms, hemorrhage, and soft tissue abscess.

Morbidity and mortality can be due to the disease process itself, with development of tumoral cell infiltration or tumor cell lysis syndrome or could be due to chemotherapy and the side effects of chemotherapeutic drug regimens.⁹

Hematologic malignancies behave like a Pandora’s box in the true sense releasing many unspecified Evils, just like mythological description of hope being left behind.

Conclusion

Understanding and anticipating the complications in leukemia and their radiological patterns of involvement can aid in early diagnosis and institution of appropriate treatment. Multidisciplinary approach is a must for cure and remission.

Financial assistance

Nil

Acknowledgements

Dr. Darshan Alizar, Dr. Riya Mehta DNB Registrars for Clinical Data and follow up of the case, and Prof P S Shankar for encouragement and editorial inputs.

Conflict of interests

Nil