When dengue meets immunosuppression: a case of severe disease in a renal transplant recipient

Abstract

This report describes a 72-year-old renal transplant recipient who presented to a Midwestern hospital with severe dengue fever after recent travel to Mexico. The patient’s clinical course was complicated by shock, mucosal bleeding, prolonged pancytopenia, and concurrent extended-spectrum beta-lactamase Eschirichia coli bacteremia. Management of this patient included selective platelet transfusions, antibiotics, and reduction of immunosuppressive therapy to support hematologic recovery. This case highlights the complexities of treating severe dengue infections in immunocompromised patients, the challenges of coinfections, and the careful use of platelet transfusions.

KEY POINTS

• Dengue in immunosuppressed patients may result in prolonged disease courses, requiring consideration of a reduction in immunosuppressive regimens to support bone marrow recovery and viral clearance.

• Concurrent bacteremia in dengue cases can possibly be explained by dengue-associated gastrointestinal permeability, highlighting a potential mechanism for secondary infections.

• Platelet transfusion thresholds in dengue should be conservative, with transfusions generally reserved for patients with active bleeding and platelet counts <10–20 k/μL due to the risk of adverse effects.

CASE SUMMARY

A 72-year-old man with a past medical history of chronic kidney disease stage IIIa with renal transplant, heart failure, atrial fibrillation, and aortic stenosis presented to our hospital with back pain, bilateral arm edema with ecchymoses, and diarrhea (Figure 1). The patient had returned from Mexico the day before, where he had been hospitalized for 5 days with dengue fever. The patient’s wife was concerned about the worsening arm edema and ecchymoses, which prompted his visit to the emergency department.

Figure 1.

Bilateral upper extremity nonpitting edema with diffuse ecchymoses and erythema noted on admission.

The patient initially presented to the hospital in Mexico with malaise, fever, arthralgias, and myalgias. After admission, he became progressively weak and anorexic, had melenic stools, and bled from his intravenous access sites. Initial laboratory findings were significant for elevated blood urea nitrogen of 145 mg/dL, creatinine of 4.56 mg/dL (baseline of 1.5 mg/dL), and platelets of 6 k/µL. Notably, the patient’s serologies were positive for dengue IgM and NS1 antigen. On day 5, he was deemed stable for discharge and was instructed to follow up with his nephrologist upon return to the US.

On presentation to our hospital, the day after discharge from the hospital in Mexico, the patient was afebrile, tachycardic, and intermittently hypotensive. Laboratory values revealed a blood urea nitrogen of 95 mg/dL, creatinine of 5.23 mg/dL, aspartate aminotransferase of 132 µL, alanine aminotransferase of 92 µ/L, white blood cell count of 2.8 k/µL (69% neutrophils, absolute neutrophil count 1.9 k/µL, 16% lymphocytes, absolute lymphocyte count 0.4 k/µL, and 10% monocytes), hemoglobin of 11.7 g/dL, red blood cells of 4.03 m/µL, and platelets of 10 k/µL. On physical examination, the patient had petechiae on his buccal mucosa, nonpitting, edematous bilateral upper extremities with diffuse, healing ecchymoses, and a mild systolic murmur. The patient was given 1 unit of platelets and bolused with fluids.

After admission, venous and arterial duplex ultrasounds of the bilateral upper extremities were normal. Blood cultures returned positive for extended-spectrum beta-lactamase (ESBL) Escherichia coli, for which the patient completed a weeklong course of ertapenem. The patient was given a bolus of 25% albumin due to hypoalbuminemia and started on maintenance fluids for presumed volume depletion, as evidenced by hypotension. He was kept on his immunosuppressive medications (tacrolimus 0.5 mg twice daily and mycophenolate 720 mg twice daily) for his renal transplant. The tacrolimus level was normal (9.8 ng/mL).

The diagnostic workup for the following “look-alike” or coinfections was negative: West Nile virus, Anaplasma, Ehrlichia, Leptospira, Salmonella, cytomegalovirus, Epstein-Barr virus, BK virus, chikungunya, and malaria. Notably, the patient was not tested for Zika virus.

On hospital day 2, approximately illness day 9, the patient reported near-resolution of his arthralgias, fatigue, and myalgias, but began bleeding from his buccal mucosa. He was transfused with 1 unit of platelets, which increased his platelet count from 16 to 55 k/µL (Table 1). Guidance from the hematology and oncology service instructed to avoid future platelet transfusions unless platelets dropped to <10 k/µL.

Table 1.

Relevant daily laboratory findings from admission to discharge

Laboratory test	Day 1	Day 2 AM	Day 2 PM	Day 3	Day 4 AM	Day 4 PM	Day 5	Day 6	Day 7	Day 8	Day 9	Day 10
Red blood cells (m/uL)	4.03	3.33	3.12	3.26	2.65	2.67	2.62	2.53	2.54	2.62	2.50	2.75
Hemoglobin (g/dL)	11.7	9.6	9.2	9.6	7.7	7.8	7.7	7.4	7.3	7.6	7.3	8.0
Platelets (k/uL)	10	16	55	28	12	10	42	26	21	30	36	74
Mean corpuscular volume (fL)	86	87	89	90	92	92	90	93	92	93	91	90
Mean corpuscular hemoglobin (pg)	29.0	28.8	29.5	29.4	29.1	29.2	29.4	29.2	28.7	29.0	29.2	29.1
Mean corpuscular hemoglobin concentration (g/dL)	33.7	33.1	33.0	32.9	31.8	31.7	32.8	31.5	31.2	31.3	32.0	32.1
Hematocrit (%)	34.7	29.0	27.9	29.2	24.2	24.6	23.5	23.5	23.4	24.3	22.8	24.9
White blood cells (k/uL)	2.8	3.0	3.1	3.5	2.7	3.0	3.8	3.7	3.7	4.4	3.3	4.7
Reticulocytes (%)				0.4
Haptoglobin (mg/dL)				<8
Activated partial thromboplastin	42.5
International normalized ratio	1.2	1.2
D-Dimer (mg/L FEU)		2.22
Fibrinogen (mg/dL)		417
CO2 (mmol/L)	18	22.0		22.0	24.0		21.0	20.0	20.0	17.0		18.0
Blood urea nitrogen (mg/dL)	95	91		66	47		36	30	28	30		24
Creatinine (mg/dL)	5.23	4.03		2.77	2.08		1.66	1.47	1.39	1.47		1.33
Albumin (g/dL)	3.4	3.2		3.0	2.7		2.7	2.6	2.5	2.5		2.6
Total bilirubin (mg/dL)	1.1	1.2		1.1	1.0		1.1	1.1	1.1	1.0		1.1
Alkaline phosphatase (u/L)	132	98		92	87		84	84	98	107		128
Aspartate aminotransferase (u/L)	132*	97		87	80		72	65	69	63		65
Alanine aminotransferase (u/L)	92	69		61	53		49	48	55	53		59
Glucose (mg/dL)	193	119		104	99		106	109	116	104		92
Protein (g/dL)	6.8	6.3		5.9	5.5		5.5	5.4	5.4	5.7		5.9

*The value resulted from a hemolyzed sample. Red text indicates an abnormal value.

Over the next 6 days, the patient’s platelets continued to drop to 10 k/µL, requiring an additional platelet transfusion on hospital day 5. The patient had one occurrence of hematuria and a recurrence of oral mucosal bleeding with clots present, which continued intermittently for 4 days. The upper-extremity ecchymoses and edema began improving after day 5. The peripheral blood smear showed decreased red blood cells, white blood cells, and platelets. Based on the available clinical data, it was determined that the patient’s pancytopenia was most likely due to dengue-induced bone marrow suppression instead of hemolytic anemia because his bilirubin was within normal limits and there was no increase in reticulocytes, and the peripheral blood smear showed normal morphology of red blood cells. Repeat dengue NS1, IgM, and IgG levels drawn on hospital day 4 all returned positive, which confirmed the diagnosis of dengue.

On hospital day 9, approximately illness day 16, platelets had improved to 36 k/µL. Given the prolonged disease duration, the transplant nephrology and infectious disease teams decided to halve the patient’s mycophenolate dosage to promote hematopoiesis.

The following day, the patient’s ecchymoses and edema of the bilateral upper extremities had nearly resolved, and there was no further mucosal bleeding. Laboratory findings were improved with a platelet count of 74 k/µL. The patient was subsequently discharged and followed up with his primary care physician and transplant nephrologist, where he demonstrated continued improvement back to baseline without further complications in his illness course.

CLINICAL QUESTIONS

1. According to the World Health Organization (WHO) criteria, which of the following best defines severe dengue?

   1. Positive dengue NS1 antigen

   2. Mucosal bleeding and hepatomegaly

   3. Pancytopenia with buccal petechiae

   4. Severe plasma leakage, hemorrhage, or organ impairment

2. Which of the following best explains the increased risk of severe dengue infection in transplant recipients?

   1. Direct viral invasion of the graft leading to rejection

   2. Prolonged viremia due to impaired viral clearance

   3. Drug interaction between immunosuppressants and dengue antivirals

   4. Increased risk of developing dengue-associated encephalitis

Answers are provided at the end of the article

DISCUSSION

In this report, we present the case of a patient with recent travel to Mexico who presented to a Midwest US hospital with clinical findings of severe dengue. Dengue is endemic throughout Mexico and, thus, providers in the US must be prepared to treat dengue given the proximity of the two countries and the ease of long-distance travel.¹

Dengue fever is a mosquito-transmitted viral infectious disease most prevalent in tropical and subtropical regions across the globe, with the Aedes aegypti mosquito being the most common vector.² There are four serotypes of the dengue virus, all of which are single-stranded positive-sense RNA viruses belonging to the Flaviviridae family.² The WHO has classified dengue into two types: severe and nonsevere. Nonsevere dengue is further classified based on the presence or absence of warning signs, which include abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, hepatomegaly, and an increase in hematocrit with a concurrent drop in platelet count.³ Severe dengue is characterized by severe plasma extravasation, hemorrhage, or organ impairment.⁴

Our patient had several classic features of dengue, including malaise, myalgias, arthralgias, thrombocytopenia, and leukopenia. Notably, he met the criteria for severe dengue based on the presence of shock.¹ Additionally, he possessed many of the “warning” signs, including edema, melena, mucosal bleeding, and hepatomegaly with transaminitis. Our patient’s >2-week symptomatic disease course was longer than the typical 2- to 7-day period. This could be attributed to the severity of the infection, the ESBL E. coli coinfection, and the patient’s immunosuppressive medication regimen. Notably, when his mycophenolate was decreased, his platelets, hemoglobin, and red blood cell counts all made the largest 1-day improvement of his hospital stay. Several case reports and studies of transplant recipients with dengue have reported improved outcomes with the reduction of immunosuppressants, but more studies are needed to determine if this is the best course of action. Other demonstrated risks of dengue infection with an underlying immunocompromising condition, in addition to changes in immunosuppressive medication dosages, include exacerbation of the underlying condition, graft dysfunction, or graft loss.⁵

Our patient’s septicemia with ESBL E. coli may have been caused by the translocation of enteric bacteria into the bloodstream due to the increased vascular permeability and gastrointestinal edema caused by dengue. Van de Weg et al documented the presence of microbial translocation in patients with severe dengue in Brazil, and other studies have shown that enteric bacteria are commonly found in concurrent bacteremia with dengue, though multidrug-resistant pathogens like ESBL E. coli are less common.^6,7 Another possibility is that the ESBL E. coli was acquired as a nosocomial infection from the patient’s stay at the Mexican hospital.

Our patient’s recovery was complicated by pancytopenia, likely due to direct bone marrow suppression, decreased platelet survival from dengue, and the patient’s immunosuppression.^5,8 Thomas et al showed that renal transplant recipients required more time for normalization of platelet counts from the nadir (6.0 ± 4.5 days) compared to controls (3.4 ± 0.9 days), which is consistent with our patient, who required over 10 days for normalization.⁹ The treatment of thrombocytopenia from dengue differs from the usual platelet transfusion threshold of ≤50 k/µL in a bleeding patient. Studies have suggested that platelet transfusions in dengue patients should be reserved for platelet counts <10–20 k/µL with active bleeding.¹⁰ Several adverse effects have been noted in patients with dengue receiving platelets, such as transfusion-related acute lung injuries, anaphylaxis, and fluid overload.¹⁰

This case provides insight into the unique management strategies involved in the treatment of critically ill, immunosuppressed patients with dengue. We have highlighted the possible role of reducing immunosuppressive medications, a possible mechanism for bacterial coinfections, and the role of platelet transfusions in dengue patients.

ANSWERS TO CLINICAL QUESTIONS

Question 1, d. The WHO defines severe dengue by the presence of severe plasma leakage, hemorrhage, or organ impairment.³ Mucosal bleeding and hepatomegaly are warning signs defined by the WHO but are not characteristic of severe dengue (answer choice b). Positive dengue NS1 antigen and pancytopenia with buccal petechiae (answer choices a and c) are common findings with dengue, but only answer d aligns with severe classification.

Question 2, b. The immunosuppressive regimens of transplant recipients blunt the immune response to the dengue virus, delaying clearance.⁵ While dengue infection could lead to graft dysfunction, dengue has not been shown to cause graft rejection (answer choice a). Dengue is not treated with antivirals, making answer choice c incorrect. Dengue encephalitis is a rare complication of dengue infection, but there is no literature to support an increased risk of dengue encephalitis in transplant recipients (answer choice d).

Disclosure statement/Funding

The authors report no funding or conflicts of interest. The patient consented to publication of this case report.