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Case 1-2021: A 10-Year-Old Male With Respiratory Failure, Pleural Effusions, and Renal Failure 60 Days After Hematopoietic Stem Cell Transplant

Loi, Michele M. MD1,2; Eissa, Hesham MD2; Weinman, Jason P. MD3; Abman, Steve H. MD4; Galambos, Csaba MD, PhD5; Carpenter, Todd C. MD1

Author Information
Pediatric Critical Care Medicine: October 2021 - Volume 22 - Issue 10 - p e524-e531
doi: 10.1097/PCC.0000000000002792
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PRESENTATION

Dr. Michele Loi (Critical Care)

A 10-year-old male with a history of severe aplastic anemia was admitted to the PICU because of increased work of breathing, fatigue, and dehydration 60 days (+ 60 d) after matched-sibling hematopoietic stem cell transplantation (HSCT).

His symptoms started 2 weeks before PICU admission with poor food intake and vomiting that persisted despite antibiotics for presumed Clostridium difficile infection. In the HSCT clinic on the day of PICU admission, he was anxious and unwell, and he was tachypneic with pulse oximetry oxygen saturation (Spo2) 85% in room air.

Dr. Hesham Eissa (Bone Marrow Transplant)

Five months before admission, the patient was diagnosed with severe aplastic anemia with normal cytogenetic testing, telomere length, and negative chromosomal fragility on testing.

The matched-sibling HSCT was without incident and involved a conditioning regimen of fludarabine, cyclophosphamide, and equine anti-thymocyte globulin. Cyclosporine and mycophenolate were used for routine graft-versus-host disease (GVHD) prophylaxis, and he was given pentamidine, acyclovir, micafungin, and cefepime for routine antimicrobial prophylaxis. On HSCT + 5 days, amlodipine was used to treat hypertension, which was thought to be secondary to cyclosporine. Platelet and neutrophil engraftment occurred on HSCT + 17 days and + 29 days, respectively, and the patient was transfusion-independent by HSCT + 37 days.

Dr. Michele Loi

At PICU presentation, the patient’s temperature was 37.6°C, with a heart rate 108 beats per minute, blood pressure 103/65 mm Hg, and respiratory rate 28 breaths per minute with Spo2 91% in supplemental nasal cannula oxygen flow 2 L/min. The patient appeared tired, but he was well perfused with normal heart sounds and rhythm. He had mild bilateral pitting edema of his feet. Breath sounds were diminished at the lung bases, and bilateral diffuse crackles were heard. His abdomen was mildly distended but nontender and without organomegaly.

Initial laboratory results are shown in Table 1. Of note, serum studies showed a rise in creatinine from a baseline level of 0.53 to 1.23 mg/dL in the last week. Lactate dehydrogenase (LDH) level was 1,699 U/L (i.e., > 2 times the upper limit of normal). The complete blood count and liver function tests were consistent with findings expected in the post-HSCT course. Blood smear showed anisocytosis without schistocytes or RBC fragments. Viral screening using polymerase chain reaction (PCR) studies for Epstein-Barr virus, adenovirus, human herpesvirus-6 (HHV-6), and cytomegalovirus were all negative.

TABLE 1. - Laboratory Values at Admission
Variable Reference Range, Pediatrics Values
Sodium (mmol/L) 134–143 140
Potassium (mmol/L) 3.4–4.7 3.8
Chloride (mmol/L) 96–109 115
Bicarbonate (mmol/L) 20–31 18
Blood urea nitrogen (mg/dL) 7–17 19
Creatinine (mg/dL) 0.23–0.61 1.23
Glucose (mg/dL) 60–105 125
Calcium (mg/dL) 8.8–10.1 9.4
Total protein (g/dL) 6.2–8.1 6.6
Albumin (g/dL) 3.7–5.6 4
Total bilirubin (mg/dL) 0.2–1.2 1.1
Alkaline phosphatase (U/L) 156–386 109
Alanine transaminase (U/L) 10–35 33
Aspartate aminotransferase (U/L) 15–40 56
Lactate dehydrogenase (U/L) 420–750 1,699
G-glutamyl transferase (U/L) 11–21 53
Magnesium (mg/dL) 1.6–2.3 1.8
Phosphorus (mg/dL) 4.5–5.5 5.3
WBC count (per uL) 5.7–10.5 7.93
Hemoglobin (g/dL) 11.1–14.5 9.0
Hematocrit (%) 32.9–41.5 27.7
Mean cell volume (fL) 75.6–85.2 91.7
Red cell distribution width (%) 13.0–15.5 20.9
Platelet count (per uL) 150–500 251
Reticulocyte count (%) 0.8–2.2 8.9

Dr. Jason Weinman (Radiology)

The chest radiograph at the time of PICU admission showed small bilateral pulmonary effusions with diffuse interstitial prominence. Two days later, the chest CT scan (without using contrast) showed ongoing interstitial prominence with marked increase in size of the pleural effusions (Fig. 1). Acknowledging the limitations of a noncontrast CT study, the main pulmonary artery (MPA) appeared enlarged and measured 22.7 mm with a corresponding aorta diameter of 15.4 mm.

Figure 1.
Figure 1.:
Serial CT chest images from the patient’s hematopoietic stem cell transplantation (HSCT) course: (A) before transplantation, (B) day + 62, (C) day + 80, (D) day + 86, (E) day + 119, (F) day + 140. Areas of interlobular septal thickening are indicated by the white arrows, and multifocal nodules are indicated by the black arrows.

Dr. Hesham Eissa

Early in the PICU admission, the patient’s creatinine improved to a nadir of 1.0 mg/dL with IV fluid hydration. By day 10 after PICU admission (HSCT + 70 d), however, his creatinine level had worsened, along with the development of mild ascites. In view of this worsening acute kidney injury (AKI), ascites and a rising reticulocyte count and LDH level, we made a presumptive diagnosis of transplant-associated thrombotic microangiopathy (TA-TMA).

Eculizumab (a complement component 5 binder) was started and resulted in adequate complement inhibition. By day 16 of PICU admission (HSCT + 76 d), the patient’s condition was worse with weight gain, hypertension, raised creatinine, and respiratory failure. We therefore weaned the dose of cyclosporine because of its possible contribution to TA-TMA and started sirolimus as an alternative immunosuppressant. Respiratory support over this period varied between the use of noninvasive positive pressure ventilation (NIPPV) and supplemental oxygen via nasal cannula.

Dr. Jason Weinman

Repeat high-resolution chest CT (HRCT) scan on HSCT + 80 days showed that the previous pleural effusions had resolved, with near resolution of previously visualized septal thickening. Another HRCT 6 days later (HSCT + 86 d) showed new changes: multifocal irregular nodules, patchy ground-glass airspace opacities, interlobular septal thickening, and moderate right pleural effusion (Fig. 1). The MPA diameter appeared enlarged in comparison with the prior HRCT but could not be precisely measured without contrast.

Dr. Michele Loi

The next day, on HSCT + 87 days, the patient underwent bronchoscopy and bronchoalveolar lavage (BAL) after endotracheal intubation. Blood-tinged secretions were found in the distal airways. The percentage of hemosiderin-laden macrophages in the BAL fluid was 0, arguing against the presence of diffuse alveolar hemorrhage (DAH). Broad infectious evaluation of the BAL fluid was negative. The patient was therefore diagnosed with idiopathic pulmonary syndrome (IPS) and so was started on etanercept and methylprednisolone. He rapidly improved, and he was extubated from respiratory support 2 days later.

On HSCT + 108 days, the patient developed acute worsening of his hypertension and had a seizure secondary to posterior reversible encephalopathy syndrome documented on MRI (Fig. 2). He also had worsening AKI and respiratory failure, which required re-escalation in respiratory support with NIPPV. Chest CT scan 11 days later (HSCT + 119 d) showed redevelopment of pleural effusions and persistent septal thickening and diffuse ground-glass opacities (Fig. 1). Echocardiograms at this time showed normal cardiac anatomy, good biventricular function with a left ventricular (LV) ejection fraction of 72%, normal septal positioning, and no atrial level shunts present. There was no evidence of pulmonary hypertension (PH).

Figure 2.
Figure 2.:
Magnetic resonance fluid-attenuated inversion recovery (FLAIR) sequence images from hematopoietic stem cell transplantation + 108 d indicating posterior reversible encephalopathy syndrome. Axial FLAIR images demonstrate patchy areas of increased signal in the left occipital and right frontal subcortical white matter, bilateral periventricular white matter, and bilateral cerebellar hemispheres (white arrows).

Progressive fluid overload was treated with initiation of continuous venovenous hemofiltration (CVVH) therapy on HSCT + 121 days, and the patient was briefly reintubated for placement of a central line, at which time bloody lower respiratory secretions were again noted. His respiratory status showed gradual improvement in response to CVVH.

The patient remained on the PICU for the next 19 days (HSCT + 140 d), when the repeat chest CT scan still showed persistent but improved ground-glass opacities without adenopathy (Fig. 1). Allowing for the limitations without contrast, the MPA diameter appeared larger than previous, now measuring 28.6 mm with a corresponding aorta diameter of 22.1 mm. Repeated echocardiograms continued to show normal biventricular function and anatomy without signs of PH. Since we did not have a clear diagnosis in the face of progressive worsening of disease despite aggressive multimodal immunosuppressive therapies, including steroids, etanercept, and eculizumab, a lung biopsy was obtained.

DIFFERENTIAL DIAGNOSIS

Dr. Michele Loi

This 10-year-old boy presented with acute respiratory failure and pleural effusions 2 months after HSCT. An undulating clinical course was complicated by TA-TMA and the need for CVVH therapy. The differential diagnoses for pulmonary disease in a post-HSCT patient fall into two broad categories: infectious or noninfectious, which are further narrowed based on the post-transplant time course of symptoms.

Infectious

After transplant engraftment, the patient can still be at risk of fungal and bacterial causes of lung infections. As a result, our patient was started empirically on cefepime and micafungin. The lengthy and vacillating course of this patient’s respiratory failure, however, would be atypical for a bacterial or fungal infection. Viral reactivation with viruses such as HHV-6 and cytomegalovirus also remained on the differential but were less likely given negative serum PCR results and negative BAL analyses. BAL was also negative for Pneumocystis jiroveci pneumonia.

Noninfectious

Early after transplant engraftment, the patient is at risk of engraftment syndrome or DAH, IPS, and pulmonary manifestations of TA-TMA. IPS is a diagnosis of exclusion since it has nonspecific clinical and imaging manifestations that may resemble an infectious process. In the late phases of the post-engraftment period (i.e., after HSCT + 100 d), cryptogenic organizing pneumonia (COP), bronchiolitis obliterans (BOS), chronic GVHD, post-transplant lymphoproliferative disease, and pulmonary veno-occlusive disease (PVOD) are seen more often, although there is overlap in the pathophysiology that can be seen between the early and late post-engraftment time periods. The patient’s chest imaging was inconsistent with diagnoses of COP and BOS, and we were unable to further narrow down a diagnosis without histology.

CLINICAL DIAGNOSIS

Post-HSCT associated IPS.

ANATOMIC DIAGNOSIS

Dr. Csaba Galambos (Pathology)

Pathology of left lingular lung biopsy showed remodeled and obstructed pulmonary veins with arterialization and tortuosity, an edematous interlobular septum, focal lymphatic dilatation and muscularization, diffuse pericapillary muscularization, and moderate pulmonary hypertensive arteriopathy with focal alveolar hemorrhage without evidence of microthrombi or signs of GVHD or interstitial inflammation (Fig. 3). Together, these findings are consistent with a diagnosis of PVOD.

Figure 3.
Figure 3.:
Patient’s lung biopsy histology. A, Trichrome stain and B, hematoxylin and eosin (H&E) stain with yellow arrows demonstrating remodeled and obstructed pulmonary veins with arterialization and tortuosity. C, H&E stain showing edematous interlobular septum. D, H&E stain showing lymphatic dilatation and muscularization. E, Smooth muscle actin stain showing diffuse pericapillary muscularization. F, Smooth muscle actin stain and (G) H&E stain showing moderate pulmonary arteriopathy. H, H&E stain showing focal alveolar hemorrhage. Scale bar = 100 µm (D, E), 200 µm (A, B, C, F, H), 400 µm (G).

DISCUSSION OF DIAGNOSIS AND MANAGEMENT

All Discussants

PVOD is a devastating and poorly understood complication of HSCT, often diagnosed late or at autopsy (1–3). PH in general is a rare complication of HSCT in children, but one that may be amenable to treatment if recognized early (4). Distinguishing arterial from venous disease in the pulmonary circulation, however, can be extremely difficult without tissue histology, and as a result, patients with PVOD may be misdiagnosed with idiopathic pulmonary arterial hypertension (PAH) (5). Indeed, our case is the first reported case of biopsy-proven PVOD in a child post-HSCT. The prevalence of PVOD in the HSCT population is unknown, although, to date, autopsy studies have shown that only a small proportion of allogeneic HSCT patients had findings of PVOD (6). Some authors have speculated on the role of pre-transplant preparative chemotherapy with alkylating agents as a likely risk factor for pulmonary vascular disease (2,3). Consistent with the observation that alkylating agents are more typically used in preparative regimens for patients with malignant disease, very few cases of pulmonary vascular disease have been reported in patients undergoing HSCTs for nonmalignant conditions. Our case demonstrates, however, that severe complications such as PVOD can also occur in patients undergoing HSCT for nonmalignant disease.

Dr. Steve Abman (Pulmonary)

PH with persistent, unexplained, or worsening pulmonary edema is consistent with post-capillary causes including LV dysfunction, pulmonary vein stenosis (PVS), or PVOD. Although echocardiogram can be useful for making the diagnosis of PH and may identify PVS in many cases, it does not reliably rule out involvement of smaller post-capillary vessels as is seen with PVOD. Making the diagnosis of PVOD and identifying the potential contribution of LV dysfunction to PH often requires cardiac catheterization. By cardiac catheterization, PVOD is characterized by the presence of elevated pulmonary artery pressure with a normal pulmonary artery occlusion pressure (PAOP) and high risk for the rapid accumulation of pulmonary edema during acute vasoreactivity testing with acute vasodilators, such as inhaled nitric oxide (iNO), whereas LV dysfunction is diagnosed by the presence of an elevated PAOP at baseline or with an acute fluid challenge.

Dr. Hesham Eissa

The causes and pathophysiology of PVOD in the HSCT population remain poorly understood. There are no large cohort studies, but alkylating agents, particularly cyclophosphamide, are the most common risk factor reported (7). Total body irradiation is also a potential risk factor (8). Our case, however, demonstrates that patients with nonmalignant disease and lower cyclophosphamide exposure may also develop PVOD. These same risk factors have also been implicated in other transplant-associated vascular complications such as TA-TMA and hepatic veno-occlusive disease, with a postulated common pathway of endothelial injury and subsequent thrombotic events (9). PVOD is likely part of the same spectrum of diseases driven by endothelial injury and subsequent vasculopathy and thrombosis. Interestingly, acute respiratory failure in our patient’s clinical course followed each episode of worsening TA-TMA and both processes—TA-TMA and PVOD—improved transiently with addition of immunomodulatory therapy, which suggests a common underlying pathophysiology.

Dr. Todd Carpenter (Critical Care)

Although the presence of PVOD may be suggested by the progressive development of PH with pulmonary edema, definitive diagnosis of PVOD relies on histology, often obtained only at autopsy. Given the risks of lung biopsy in patients with pulmonary vascular disease, the best approach to diagnosing pulmonary venous disease is not clear, and as a result, the diagnosis is often missed or delayed.

Two critical issues during PICU management of patients with post-HSCT acute respiratory failure are: 1) deciding on the most likely clinical diagnosis and, therefore, determining the most appropriate treatment and 2) deciding when it is apparent that the patient is failing to respond to management and, therefore, moving on to a tissue diagnosis with lung biopsy. The classic triad of CT findings in PVOD includes mediastinal lymph node enlargement, centrilobular ground-glass opacities, and, if IV contrast is given, diffuse thickened interlobular septa (10–12). Our patient had serial echocardiograms that were persistently normal even as the lung disease continued to progress. Chest CT studies, however, suggested some enlargement of the MPA with worsening parenchymal infiltrate, suggesting the presence of PH and worsening pulmonary edema. As these features are not sufficient to diagnose PVOD, we progressed to lung biopsy, especially in light of the worsening lung disease and our concerns for the presence of an undiagnosed infection despite the negative noninvasive diagnostic studies. We accepted that the potential benefits to treatment outweighed potential risks associated with thoracoscopic biopsy, which may be significant in patients with severe PH.

Dr. Michele Loi

To date, there are only a few reports of lung biopsy findings in TMA-associated PVOD. Diagnostic lung biopsies can often lead to changes in care (83%) with no mortality linked directly with the biopsy itself (13). The disease can affect veins of all calibers and normal veins can be seen on pathology, depending on patchy or diffuse involvement of disease (11). The histology of PVOD is characterized by intimal fibrosis and muscularization of the vascular wall in normally nonmuscular veins that both occludes and narrows the pulmonary venous lumen. The other findings are thought to be compensatory responses to the presence of post-capillary obstruction and passive venous congestion. Edematous interlobular septa are seen due to dilation of lymphatic spaces from increased hydrostatic pressure, and venous infarcts can be seen parallel to occluded veins. Alveolar capillary dilatation and hypertrophy lead to interstitial fibrosis, capillary hemangiomatosis, and areas of hemorrhage. Alveolar hemosiderin-laden macrophages can be found in these spaces. Precapillary pulmonary arteries become muscularized due to increased pressure, creating both pre- and post-capillary causes of PH in advanced PVOD (8,14–16).

Besides supportive measures, there are no standard treatments for PVOD and prognosis remains grave. Vasodilators used for PAH (e.g., phosphodiesterase-5 inhibitors and calcium channel blockers) may attenuate the contribution of precapillary PH, but these agents can worsen pulmonary edema in many PVOD patients, leading to an increased need for diuretic therapy or ventilatory support. Immunosuppression with steroids, cytotoxic agents, and tyrosine kinase inhibitors has been used in subjects with PVOD but with no clear evidence of efficacy (17,18). Anticoagulation may seem a reasonable option given the thrombotic features of PVOD on histology, however, efficacy is unproven, and the risk of worsening underlying hemoptysis and hemorrhage needs to be considered. TA-TMA-directed therapies such as eculizumab and defibrotide (4) have also been proposed as therapies and are currently under investigation. Ultimately, lung transplant is the only definitive therapy that may offer survival benefit, but this can be a difficult choice in the post-HSCT patient.

Taking all of the above together, our experience shows that PVOD should be considered in the differential diagnosis of hypoxemia in the post-HSCT patients with an underlying nonmalignant disease, as well as patients with malignancies.

FOLLOW-UP

Dr. Steve Abman

Echocardiographic findings of PH rapidly progressed late in the course. Earlier studies were normal despite concomitant chest CT changes suggesting enlargement of the MPA with worsening lung infiltrate before the lung biopsy. It is noteworthy that such striking pulmonary arterial and venous structural changes preceded echocardiographic evidence of PH in this case, suggesting that severe PVOD was already present prior to evidence of PH by echocardiography.

Dr. Michele Loi

A trial of iNO was initiated and resulted in a transient increase in Spo2 from 70% to 90% for 24 hours, along with improved right-sided heart pressure. Unfortunately, pulmonary edema worsened, which is typical for PVOD and is likely due to increased flow from precapillary dilation in the setting of concurrent post-capillary disease. This physiology led to progressive hypoxemia and worsening lung mechanics, which in the face of severe underlying disease, led to the patient’s death on HSCT + 167 days.

Dr. Todd Carpenter

Interestingly, heritable PVOD with autosomal recessive transmission and variable penetrance has been linked to mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene, and cases have been reported from infancy to adulthood. A 33% 2-year survival rate has been reported for PVOD cases linked to eukaryotic translation initiation factor (EIF) mutations (19). Postmortem genetic testing for EIF gene mutation was discussed with the family in our case but was declined.

Dr. Csaba Galambos

Autopsy postmortem again showed findings consistent with PVOD comparable to the previous biopsy with alveolar edema, hemorrhage, and fibrin disposition. The lungs were three times heavier (right lung 603 g, left lung 504 g) compared with expected mean weights for age and sex (right 177 g, left 166 g). The heart was enlarged (260 g compared with expected mean weight 116 g) due to severe right ventricular dilation with increased mitral and tricuspid valve circumference (both measured at 10.5 cm compared with the expected means of 7.3 and 8.7 cm, respectively) and focal pleural vessel prominence. There was evidence of renal glomerular changes that were consistent with a history of TMA and acute tubular injury.

FINAL DIAGNOSIS

PVOD in the setting of TA-TMA.

REFERENCES

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Keywords:

aplastic anemia; hematopoietic stem cell transplant; lung biopsy; pulmonary hypertension; pulmonary veno-occlusive disease; respiratory failure

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