Fatal co-infection by multiple pathogens in an indigenous woman with autoimmune hemolytic anemia and tuberculosis: a case report – BMC Infectious Diseases

An indigenous 28-year-old woman from Guaviare, a southern-central region state of Colombia originally inhabited by the indigenous Nukak people, presented to a local hospital with a 15-day history of fatigue, shortness of breath and tensional headache. She had a 2-year medical history of AIHA, due to mixed autoantibodies of unknown etiology, with a daily oral treatment of azathioprine (50 mg) and prednisolone (25 mg) since diagnosis. In addition, an extra-institutional report indicated that 10 months ago the patient was diagnosed with pulmonary TB following positive serial bacilloscopy and the isolation of M. tuberculosis, resistant to isoniazid, from sputum culture. During this episode of TB, the patient did not receive any treatment owing to limited access to antimycobacterial agents. It was also unknown if screening for latent TB was done before the diagnosis of AIHA. She did not report fever, weight loss, cough, or any other symptoms. Because of her medical history, a complete blood count and a hemolytic anemia workup were performed, finding a hemolytic crisis (hemoglobin 4.9 g/dL, lactate dehydrogenase (LDH) > 1000 U/L and indirect hyperbilirubinemia) but normal leukocytes and platelets counts. Due to her condition, she received a blood transfusion and high-dose intravenous methylprednisolone without any response. Therefore, she was referred to a fourth level hospital for integrated clinical management.

At admission to our hospital, cyanocobalamin and folic acid deficiency, HIV infection, hepatitis B and C, syphilis, and hemolytic anemia secondary to autoimmune diseases such as systemic lupus erythematosus, were ruled out. A chest radiography did not show any apparent lung abnormalities. At day 5, the patient presented hemodynamic instability and was admitted to the intensive care unit (ICU). Considering the null response to methylprednisolone, the worsening of anemia and the persistence of an active hemolytic profile, another blood transfusion and management with four doses of anti-CD20 (rituximab), were indicated. Unfortunately, refractoriness to this therapy was reported, therefore management with a four-dose cyclophosphamide (CYC) scheme was added. Due to hematological toxicity manifested as pancytopenia, the last CYC dose was not administered.

During her ICU stay, the patient developed several secondary infectious complications, starting with oral and vulvovaginal mucositis and multiple-organism bacteremia (MOB) with isolation, from blood, of Escherichia coli, methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecium vancomycin susceptible. Consequently, she was indicated with multiple antibiotic schemes including ceftaroline fosamil and ceftazidime-avibactam plus aztreonam combination.

Despite multiple antibacterial treatments and even though her LDH and total bilirubin levels normalized, the patient persisted with febrile neutropenia and deeper cytopenia. Considering that the patient was not receiving any myelosuppression drugs, there was suspicion of bone marrow infection by atypical microorganisms. Therefore, bone marrow biopsy and myelocultures were ordered to determine the presence of pathogens in this tissue or a hidden neoplasia. Pathological investigations reported a hypocellular (10%), subcortical and fragmented bone marrow without infiltration. Iron, Grocott methenamine-silver and periodic acid-Schiff stains, as well as Rose Bengal test and myelocultures were negative. Nevertheless, given the persistence of fever and bone marrow aplasia, antimicrobial coverage against intracellular pathogens that could compromise bone marrow function, was indicated. This combined therapy included clindamycin, doxycycline, ivermectin and azithromycin. Specific tests for parvovirus B19 and malaria were found negative. PCR for TB of a bone marrow aspirate was negative too. Even though herpes simplex virus 2 IgG and cytomegalovirus viral loads were detected in blood, neither clinical nor symptomatic improvement of the patient was observed after treatment with acyclovir and ganciclovir.

While conducting additional studies, the patient presented gross hematuria. A urinalysis reported proteinuria, hematuria, glycosuria, and active sediment. A computerized tomography (CT) scan of the urinary tract revealed bilateral nephromegaly. Additionally, nephrotic-range proteinuria was documented, with indication for renal biopsy, which was deferred due to the severe aplasia. Considering these findings, the patient’s origin, and the medical history, there was a high suspicion of genitourinary TB. However, a PCR for TB in urine gave a negative result.

As the patient persisted with severe bone marrow aplasia associated with complications by MOB, a second bone marrow biopsy was performed as well as myelocultures and hemocultures, to ruled out deep mycoses. At first, bone marrow biopsy pathology revealed suggestive blastoconidia (Fig. 1), therefore, liposomal amphotericin B was indicated with poor response. Hematolymphoid neoplasms was not observed. Afterwards, both from bone marrow and blood, Candida glabrata was isolated, switching the antifungal treatment to caspofungin. Klebsiella pneumoniae carbapenemase (KPC)-producing was also recovered from bone marrow and blood samples. A PCR and Ziehl-Neelsen stain for M. tuberculosis in bone marrow were reported negative.

A CT scan of the lungs revealed alveolar opacities, pleural effusion and cardiomegaly (Fig. 2). Considering the medical history, TB tetraconjugated treatment plus moxifloxacin was indicated. Given the high complexity of this case, a medical board, including critical care, infectious diseases, hematology and pneumology specialists, was held. It concluded that the medullary aplasia has multiple causes, being secondary to myelotoxicity by immunosuppressive therapy, due to AHIA, and infectious diseases including TB, with pulmonary involvement, as well as MOB by antibiotic-resistant bacteria, and bone marrow mycosis and candidemia by C. glabrata, which was resistant to caspofungin, as established later (MIC of 64 µg/ml).

Computer tomography scan of the chest of a 28-year-old indigenous woman with tuberculosis, autoimmune hemolytic anemia and multiple pathogen co-infections. (A) Multifocal alveolar opacities. (B) Pleural effusion, more extensive on the right side, and cardiomegaly

Despite polymicrobial treatment and multiple red blood cell and platelet transfusions, due to anemia and thrombocytopenia, the patient was in a poor general condition, tachycardic, polypneic and required continuous positive airway pressure (CPAP) therapy. In addition, pancytopenia and neutropenia persisted, in spite of the administration of filgrastim. Given that the severe aplasia could not be resolved, the patient presented hemodynamic and respiratory failure, with indication for invasive mechanical ventilation. However, she refused invasive procedures including cardiopulmonary resuscitation or intubation. At day 114, the patient died because of acute respiratory failure. Autopsy revealed the presence of 45-degree angled, branching hyphae, suggestive of Aspergillus, in lungs and kidneys. After her death, a relative of the patient informed that she was a close contact of two people with TB, from whom one died of this mycobacterial infection.