CD4 lymphopenia with respiratory failure
Question:
2/10/2020
A 56-year-old white male who was admitted 2 weeks ago with a low CD4 absolute cell count of 56—HIV negative. CD 19 cells slightly low, but not far from normal. T-cell lymphocyte mitogen panel is pending. Remainder of his immune evaluation shows a low IgM and low pneumococcal antibodies in all serotypes. DHR, neutrophil killing studies are normal; complement is normal. His serum ferritin is 4000. The remainder of his evaluation has shown no malignancy peripherally or in bone marrow biopsy. He does have some aspiration and a progressive granulomatous pulmonary infiltrate. He is now intubated secondary to respiratory failure and sepsis. I have genetic studies that are pending.
His hospital assessment from today is as follows:
1. Sepsis with multiorgan dysfunction syndrome–undefined source
2. Refractory hypoxemic respiratory failure
3. Extensive pulmonary remodeling–present on admission
4. Elevated transaminases–probable ischemic transaminitis
5. Acute kidney injury
6. Hyperphosphatemia–likely related to #5
7. Anemia with progression
8. Recent coagulopathy
9. Recurring fevers
10. Previous treatment for histoplasmosis and sarcoidosis
11. MSSA positive BAL
12. Underlying immunodeficiency
13. Multiple masslike pulmonary densities including a new right lower lobe lesion
Any additional suggestions as to evaluation or treatment?
Answer:
This is a very complex patient with many issues, the most pressing of which is respiratory failure and probable systemic inflammatory response. The profoundly low CD4 count suggests acute infection, chronic infection, lymphoma or other hematologic malignancy or idiopathic CD4 lymphopenia with secondary infection. The history of sarcoidosis “treatment” would suggest to me an increased risk of lymphoma as the adenopathy may have been misattributed to sarcoidosis.
The prior treatment for histoplasmosis coupled with the low CD4 lymphopenia suggests that the acute respiratory failure may be due to fungal infection, despite the lavage apparently not showing. Other considerations would be an overwhelming viral infection such as influenza, adenovirus, parvovirus B19, coronavirus, cytomegalovirus, herpesvirus-6 and respiratory syncytial virus. The increased ferritin and prolonged hospitalization raises the possibility of hemophagocytic lymphohistocytosis (HLH). This condition can be familial or related to specific genetic defects (primary) or secondary to viral illness or lymphoma. HLH could cause the abnormal liver function tests.
I would suggest the following:
1. Careful review of HIV testing to be sure HIV1 and HIV2 are excluded as well as HTLV-I and -II if from areas of the world in which the latter infection occurs. I suggest not relying on serology but utilize PCR.
2. Review of bronchial lavage with careful search for atypical and typical TB, fungal infection and viral studies with PCR for the latter.
3. Consider clonal studies on peripheral blood lymphocytes and obtain NK cell number/function in light of possible HLH.
4. Obtain genetic testing panel for primary HLH.
5. Consider biopsy of the lung mass looking for infectious agent or malignancy, particularly lymphoma.
6. Check for soluble CD25 and triglycerides (increased in HLH) and fibrinogen (decreased in HLH).
7. Flow cytometry for NK cell perforin or CD107 alpha or a NK cell cytotoxicity assay.
In summary, I suspect the presentation is systemic inflammatory response secondary to an opportunistic lung infection but would also strongly consider HLH. If systemic corticosteroid therapy has not already been initiated, I would suggest dexamethasone IV 10 mg/m2 daily pending the results of the tests (1).
1. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol.
Trottestam H, Horne A, AricòM, Egeler RM, Filipovich AH, Gadner H, Imashuku S, Ladisch S, Webb D, Janka G, Henter JI, Histiocyte Society, Blood. 2011;118(17):4577. Epub 2011 Sep 6.
Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for≥5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54%±6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66±8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50%±13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy>1-year without HSCT; they presented at older age (P<.001), were more often female (P = .011), and less often had CNS disease (P<.001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.
I hope this information is of some help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI