Case Presentation: A 36-year-old male with a history of B-cell acute lymphoblastic leukemia (ALL) treated with Hyper-CVAD with intrathecal chemotherapy and allogenic hematopoietic stem cell transplant (HSCT) from a haploidentical donor (CMV D-/R+). His ALL relapsed 8 months after transplant and he subsequently underwent pre-phase chemotherapy for future CAR T-cell therapy, developing pancytopenia. He was ill since starting his latest therapy, but after exposure to a sick child, he presented with acute and severe shortness of breath requiring intubation. He was febrile to 39.3°C and leukopenic at 0.2 cells/mm³. Empiric therapy with vancomycin, cefepime, tobramycin and micafungin were started. CT chest imaging was interpreted as severe multifocal pneumonia. Infectious workup yielded positive RSV nasopharyngeal PCR, Streptococcus pneumoniae growth from BAL, negative blood cultures, and negative 1-3-ß-D glucan. Despite broad spectrum antimicrobials, the patient deteriorated. On day 5, repeat 1-3-ß-D glucan and serum Galactomannan antigen returned elevated at 96 pg/mL and 3.103 respectively. ID was consulted for approval of anti-mold therapy with Cresemba. Our interpretation of his initial imaging was that at least one consolidation was a macronodular opacity with surrounding halo sign, suggesting earlier radiographic evidence of invasive pulmonary aspergillosis (IPA). ID recommended initiation of liposomal amphotericin B for probable IPA with evaluation for possible treatment for RSV with ribavirin. Despite this, he succumbed to his illness the following day.

Discussion: Severe respiratory infection (SRI) is a leading cause of respiratory failure in immunocompromised patients – the incidence for bacterial pneumonia is 33%, viral 30%, fungal 15% with the remaining being non-infectious. Early treatment is critical to reduce morbidity and mortality, however it can hinder identification of the causative organism by 50% [1]. Diagnosis of SRI in this population is challenging, in part since immunocompromised patients may have bacterial, viral and/or fungal co-infections. Physicians must cautiously interpret radiographic and laboratory studies as well as maintain a high suspicion when evaluating other causes in patients who fail to improve on appropriate therapy. In our case, treatment was focused on the diagnosis of pneumococcal pneumonia, however there were radiographic findings sufficient for a diagnosis of probable IPA. Although the 1-3-ß-D glucan was initially negative, studies have shown the sensitivity of this assay ranges between 50% and 80%, and common causes of false negative B-D glucan assays are hemolysis and lipemia which were present [2,3]. As IPA carries a high mortality, earlier recognition would have led to earlier therapy and potentially impacted his overall clinical course. This case is an example of how immunocompromised patients can present with concurrent and unusual infections. It is vital for physicians to search for additional sources, especially in the setting of continued deterioration with low barriers to initiating empiric treatment.

Conclusions: We present a case of an immunocompromised host with a history of an allogenic HSCT for B-cell ALL with concurrent RSV, pneumococcal pneumonia, and IPA. Diagnosing SRI in immunocompromised patients is challenging due to many infectious and non-infectious causes. Laboratory and radiological studies are helpful, however are not always diagnostic due to the sensitivity and specificity of testing.