Case-Based Review

Management of Early Pulmonary Complications After Hematopoietic Stem Cell Transplantation

2018 January/February;13(1):36-48

References

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Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.