Pulmonary complications are common in children following hematopoietic cell transplantation (HCT) and contribute to morbidity and mortality in the post-HCT phase (1–3). Early identification, diagnosis, and treatment of these complications are essential to limit morbidity and improve outcome. However, diagnosis can be quite challenging as etiologies can overlap and obscure diagnosis. In such complicated cases, laboratory testing and diagnostic imaging may not establish diagnosis and further invasive diagnostic testing such as bronchoscopy and lung biopsy might be needed. We report a 12-year-old girl who developed recurrent episodes of respiratory distress requiring intensive care unit (ICU) admission in the post-HCT phase and describe the diagnostic challenges and the multidisciplinary approach that is crucial in similar situations. Furthermore, we present a review of the diagnostic approach of pulmonary complications post-HCT and highlight the utility of bronchoscopy and lung biopsy to establish diagnosis in these children.

A 12-year-old female patient with a history of T-cell acute lymphoblastic leukemia presented to our ICU on Day +38 after her second haploidentical HCT due to a failed extubation in the OR post bronchoscopy. Our patient had previously undergone a haploidentical HCT with prep regimen consisting of fludarabine, thiotepa, melphalan, cyclophosphamide and rabbit ATG followed by a TCRα/β+ and CD19+ depleted graft infusion. GCSF was administered until engraftment and CD45RA-depleted donor lymphocyte infusion was given post engraftment for immune reconstitution. Our patient’s first haploidentical HCT was complicated by Cytomegalovirus (CMV) viremia and acute grade II gastrointestinal graft versus host disease (GVHD). CMV reactivation was treated with ganciclovir, foscarnet and cytogam administration and GVHD became quiescent with oral budesonide and beclomethasone. She had a CNS relapse on Day +150, with subsequent bone marrow relapse. She underwent remission induction chemotherapy and proceeded to have a second haploidentical HCT. During her second HCT, she received reduced intensity conditioning with fludarabine, thiotepa, melphalan, cyclophosphamide, and rabbit ATG, followed by a TCRα/β+ depleted graft and subsequent memory T cell infusion (CD45A+ depletion). Our patient’s second HCT was complicated by CMV reactivation requiring ganciclovir therapy as well as rising LDH, complement level (CH50), proteinuria, and acute kidney injury suspicious for transplant-associated thrombotic microangiopathy (TMA). She was started on eculizumab on Day +8 after her second HCT and achieved engraftment on Day +11. Engraftment was complicated by fevers and hyperferritinemia suspicious for secondary hemophagocytic lymphohistiocytosis treated briefly with Anakinra that was discontinued since she did not meet criteria for diagnosis of hemophagocytic lymphohistiocytosis. She was switched from sirolimus to ruxolitinib for GVHD prophylaxis. She developed a brief oxygen requirement on Day +20, which responded well to diuresis and she was discharged to home on Day +34. On Day +37 she was readmitted with tachypnea, a new oxygen requirement, and a diffuse bilateral airspace disease on chest x-ray (Figure 1A). A bronchoscopy was performed on day +38 to evaluate for an infectious etiology after elective intubation, and she was successfully extubated on Day +39. Broncho-alveolar lavage fluid was PCR positive for CMV, but no other infectious source was identified. Her ganciclovir was switched to foscarnet with cytogam added to improve coverage. Her condition improved and she transferred back to the HCT ward on Day +44. On Day +49, she was readmitted to the ICU with worsening hypoxia. CT scan showed diffuse ground glass appearance with air trapping in the lower lobes (Figures 1B, C). Despite serum CMV titers remaining low, her respiratory status continued to worsen. Lung biopsy by video-assisted thoracoscopic surgery (VATS) was performed on Day +55 due to uncertainty surrounding her diagnosis. Her lung biopsy demonstrated organizing pneumonia with patchy consolidation (Figure 2A), characterized by prominent fibroblastic proliferation in terminal airways and numerous macrophages occupying airspaces, compatible with cryptogenic organizing pneumonia (COP) (Figure 2B). An occlusive arterial thrombus was noted (Figure 2C), a possible sequela of TMA. Given these biopsy findings, she was started on methylprednisolone 1 mg/kg/day for COP. Steroids were well tolerated and were tapered over a period of 4 months. Her eculizumab dosing was increased to twice per week for better control of her TMA, and imatinib was added to prevent progression of fibrosis. Her respiratory status slowly improved, and she was transitioned back to the HCT unit on Day +73, with stable settings on bilevel positive airway pressure (BIPAP) support at night and minimal (1–2 liters/min) supplemental nasal cannula oxygen during the day. She was discharged to home on Day +84 with the same level of respiratory support. Imatinib was discontinued on day +169 and she was continued on Ruxolitinib. Clinical assessment on her last follow-up on day +315 showed continued improvement in her lung function with tolerance of her gradual wean of the BIPAP support. Her clinical course is summarized in Figure 3.

Pulmonary complications post-HCT can be related to infectious or non-infectious etiologies. Infections causing pneumonia or ARDS can occur at any stage during the HCT course. However, infectious organisms will vary with the specific immune deficiency, whether humoral or cellular, depending on the timing of transplant. The rate of infectious complications has decreased with better strategies for pre-emptive testing and surveillance as well as use of antimicrobial prophylaxis. However, the incidence of non-infectious lung injury is still on the rise. Late onset non-infectious pulmonary complications usually follow a more predictable timeline after HCT (Table 1) (1, 4–9).

The pulmonary function testing (PFT) is done routinely before HCT to assess baseline lung function. PFT does not usually have a role in early diagnosis of these pulmonary complications. However, PFT can be useful as a follow-up tool to assess response to therapy as well as a prognostic tool. BOS is characterized by an obstructive pattern with FEV1/FVC (forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) ratio) <0.7 and FEV₁ <75%. COP is characterized by a restrictive pattern with TLC less than the fifth percentile and normal FEV₁/FVC (3).

Bronchoscopy with bronchoalveolar lavage (BAL) is usually performed with the acute onset and persistence of respiratory symptoms after antimicrobials initiation. In addition, if diffuse alveolar hemorrhage is highly suspected, BAL can confirm the diagnosis by retrieving sequential bloodier aliquots with BAL. Diagnostic yield of BAL in children post-HCT ranges from 30 to 67% and results in change of therapy in 34–68% of cases (Table 2). Viral and bacterial organisms are the most detected; the most common virus identified is CMV. Many factors can reduce the yield of this procedure, including duration of antimicrobial therapy before the procedure (30), acute GVHD GII-IV, and immunosuppressive therapy at the time of BAL (31). In a cohort of 57 post-HCT patients, shorter time between abnormal CXR and the BAL correlated with positive yield (2 days vs 6 days in patients with negative yield) (33). BAL yield is reported to be 2.5× higher when done within 4 days of presentation compared to later, and as high as 75% when performed within 24 h (38). Complications are reported in 1–31% of patients but are usually mild and short lived. Common complications include mild, transient hypoxia and bleeding. Recent introduction of metagenomic sequencing of these samples is promising and may increase the BAL yield by detecting a causative pathogen (39).

Approximately 35% of pediatric HCT patients undergo BAL, and less often lung biopsy (8%) (34). Which procedure gives the most helpful diagnostic information with the lowest complication rate remains to be answered. Many studies have compared both procedures in immunocompromised children but found no consensus on the superiority of one procedure (30, 50). In a study that compared BAL to lung biopsy in a pediatric cohort post-HCT, the diagnostic yield of BAL was 40% compared to 94% with lung biopsy. The median days of intubation was 8.5 days in the BAL group compared to 4 days in the lung biopsy group (34). A meta-analysis of 95 studies in cancer and HCT patients (both adult and children) compared the efficacy and complications of BAL vs lung biopsy. Non-infectious etiology was diagnosed in lung biopsy more often than BAL; however, the rate of complication was higher in the lung biopsy group compared to the BAL group (0.15 vs 0.008) (51).

The decision of which procedure to choose depends on the situation and often requires a multidisciplinary team discussion among transplant, infectious, pulmonary, surgical, radiology, and ICU teams. If an infection or DAH is suspected, BAL is often the initial diagnostic approach. However, in some instances, even with the detection of a pathogen on BAL and giving appropriate treatment, respiratory status may not normalize. In these situations, multifactorial etiologies may be present and lung biopsy can likely establish other diagnosis. In addition, SLB should be the initial diagnostic tool when COP, BOS, pulmonary fibrosis, and/or treatment toxicity are suspected.

Diagnosis of pulmonary complication post-HCT is complex and often requires a multidisciplinary approach. Initial diagnostic imaging may suggest the etiology of the pulmonary process. However, in many instances, further diagnostic testing such as BAL or lung biopsy is needed. BAL is useful for diagnosis of infectious pulmonary complications; however, lung biopsy is superior for diagnosis of non-infectious pulmonary complications. Benefits and risks of these procedures should be considered thoroughly, but an early decision aids in early identification and treatment of the pulmonary process and prevents further lung damage.

LE and AQ: conceptualization. LE, JM, CM, HA, MM, RR, SS, and AQ: writing—review and editing. All authors have reviewed and approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. All authors contributed to the article and approved the submitted version.

This research was funded by the American Lebanese Syrian Associated Charities (ALSAC).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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