COVID‐19 in solid organ transplant recipients

Abbreviations

ARDS

acute respiratory distress syndrome

COVID‐19

coronavirus disease 2019

IL‐6

interleukin‐6

KT

kidney transplant

LDH

lactate dehydrogenase

SLK

simultaneous liver‐kidney transplant

To the Editor,

First identified in December 2019, the novel severe acute respiratory syndrome coronavirus‐2 has spread widely. ¹ , ² Coronavirus disease 2019 (COVID‐19) was declared a pandemic in March 2020. Post‐transplant patients appear to be particularly vulnerable. ³ , ⁴ , ⁵ , ⁶ , ⁷

University of Arkansas for Medical Sciences (UAMS) is the only abdominal transplant institution in the state of Arkansas. Between March 25 and April 20, four transplant recipients with functioning grafts tested positive for COVID‐19. Three were African American; one was Hispanic. Median age was 62.5 years (range 49‐65). Three patients had received kidney transplant (KT). One had received a simultaneous liver‐kidney (SLK). All patients were hypertensive; half were morbidly obese. The SLK recipient was also diabetic with chronic kidney disease. None was a smoker. The median time since transplant was 292 days (range 70‐523) (Table 1). All patients had been on tacrolimus and an antimetabolite. All but the SLK patient had been on prednisone.

Table 1.

Patient demographics

Patient	Age	Gender	Race	Type of transplant	Donor type	Time from transplant to infection (days)	Comorbid conditions	Tobacco	F/u (days)
1	49	F	AA	DDKT	DBD	314	HTN, morbid obesity, hyperthyroidism	No	52
2	64	F	AA	DDKT	DBD	523	HTN, morbid obesity, MGUS, SVC stenosis, AMR	No	39
3	61	M	Hispanic	SLK	DBD	70	HTN, DM, CKD, hypothyroidism	No	43
4	65	F	AA	DDKT	DBD	270	HTN, renal cell carcinoma	No	26

Abbreviations: AA, African American; AMR, antibody‐mediated rejection; CKD, chronic kidney disease; DBD, donation after brain death; DDKT, deceased donor kidney transplant; DM, diabetes mellitus; F, female; f/u, follow‐up; HTN, hypertension; M, male; MGUS, monoclonal gammopathy of unknown significance; SLK, simultaneous liver‐kidney transplant; SVC, superior vena cava.

The most common symptoms were fever, sore throat, and shortness of breath (75% of patients) (Table 2). Half patients reported fatigue, rhinorrhea, headache, cough, and nausea. Altered taste/ smell or diarrhea was reported by one. 75% had contracted COVID‐19 by a family member. ¾ patients were hospitalized. At a median follow‐up of 41 days (range 26‐52), three patients have recovered. One developed acute respiratory distress syndrome (ARDS), was placed on mechanical ventilation, and eventually succumbed.

Table 2.

Initial presentation, course, and laboratory findings

Pt	Exposure	Presenting symptom	Fever	CXR findings	CT findings	WBC initial/nadir (K/µL)	L (%) a	D‐dimer (ng/mL) a	Ferritin (ng/mL) a	Troponin (ng/mL) a	CRP (mg/dL) a	IL‐6 (pg/mL) a	LDH (IU/L) a	PCT (ng/mL) a	O2	Disp.
1	Husband (first responder)	Sore throat, SOB, fatigue, headache, rhinorrhea	No	N/A	N/A	4.5/3.8	32.1/ 36.6/ 36.6	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	Remained home
2	Unknown	Fever, sore throat, SOB, cough	Yes	Diffuse b/l air‐space disease	RLL consolidation, focal mass‐like consolidation in posterior segment of RUL, diffuse consolidation of LLL	4.0/0.82	0.7/ 0.66/ 0.29	1600/ 25 671/ 14, 975	1314/ >15 000/ >1500	0.66/ 0.66/ 0.12	164.3/ 371/ 116.1	7779.8/ 49 517.0/ 499.3	211/ 3627/ 3627	3.69/ 37.02/ 37.02	MV, trach	ICU/Death
3	Wife	Fever, sore throat, cough, fatigue, rhinorrhea, headache, nausea, diarrhea, altered taste & smell	Yes	Subtle air‐space disease in the LLL	N/A	1.67/ 0.76	0.43/ 1.26/ 1.26	732	1125/ 1914/ 1914	<0.03/ 0.07/ <0.03	146.6/ 152.4/ 87.3	N/A	455/ 508/ 332	0.14/ 0.17/ 0.10	No	D/c home
4	Daughter, (grandson had exposure at daycare)	Fever, SOB, Fatigue, cough, nausea, diarrhea, poor appetite	Yes	Min bibasilar atelectatic change	N/A	3.91/ 2.83	0.53/ 1.4/ 1.4	14 470	2164/ 4318/ 1976	0.03/ 0.04/ 0.04	18.3/ 78.3/ 14.4	N/A	331/ 448/ 367	0.13/ 0.35/ 0.35	NC	D/c home

Abbreviations: b/l, bilateral; CRP, C‐reactive protein; CXR, chest x‐ray; Disp; disposition; ICU, intensive care unit; IL‐6, interleukin‐6; L, lymphocyte count; LDH, lactate dehydrogenase; MV, mechanical ventilation; N/A, non‐applicable; NC, nasal cannula; PCT, procalcitonin; RLL, right lower lobe; RUL, right upper lobe; SOB, shortness of breath; WBC, white blood cell count.

^a Admit, peak, terminal.

Three patients were lymphopenic on initial presentation. Inflammatory markers were measured on inpatients. All patients had ferritin levels higher than 1300 ng/mL, c‐reactive protein (CRP) above 5 mg/dL, and lactate dehydrogenase (LDH) higher than 200 IU/L. Troponin was above 0.5 ng/mL on the ARDS case (Table 2).

All patients had received immunosuppression induction (Table 3). Half had received antithymocyte globulin. The ARDS patient had received basiliximab; that patient had had a history of monoclonal gammopathy of unknown significance and had received plasma exchange for antibody‐mediated rejection.

Table 3.

Immunosuppression, antiviral, and antimicrobial treatments

Patient	Organ type	Time from transplant to infection (days)	Induction	CNI	Antimetabolite	Total daily dose (mg)	mTOR	Prednisone (mg)	Immunosuppression changes	COVID19 directed therapy	Antimicrobial agents
1	DDKT	314	ATG	FK	MPA	720	N/A	5	d/c MPA	Azithro
2	DDKT	523	Basiliximab	FK	MMF	500	N/A	5	d/c FK, MMF	Tocilizumab, azithro, HQC	Cefepime, linezolid, levofloxacin, vancomycin, meropenem, fluconazole, micafungin, amikacin, zosyn,
3 a	SLK	70	Basiliximab	FK	MPA	1440	N/A	N/A	d/c MPA, decrease FK	HQC, azithro	Cefazolin, vanc, cefepime, metronidazole, nystatin
4	DDKT	270	ATG	FK	MMF	1000	SRL	5	d/c FK, MMF and SRL; SRL was resumed while inpatient	HQC, azithro	Levofloxacin, metronidazole, fluconazole, cefepime, vanc

Abbreviations: ATG, antithymocyte globulin; azithro, azithromycin; d/c, discontinue; FK, tacrolimus; HCAP, healthcare‐associated pneumonia; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MPA, mycophenolic Acid; mTOR, mammalian target of rapamycin inhibitor; PNA, pneumonia; SRL, sirolimus; UTI, urinary tract infection; vanc, vancomycin; zosyn, piperacillin‐tazobactam.

^a Patient had received plasma exchange × 6 in 11/2018 for the treatment of antibody‐mediated rejection.

There is currently no proven COVID‐19 treatment. ³ , ⁸ With the assumption that T‐cell depression poses patients to higher viral infection risk, antimetabolites were discontinued. ⁹ Tacrolimus was withheld on hospitalized patients. ³ , ⁴ , ¹⁰ , ¹¹ Azithromycin and hydroxychloroquine were administered to all hospitalized patients. ¹² , ¹³ , ¹⁴ , ¹⁵ On the ARDS patient, D‐dimer and IL‐6 were very high, corroborating reports of high D‐dimer and IL‐6 association to dismal outcome. ¹⁶ The patient received tocilizumab which reversed IL‐6 up‐trending yet did not alter the outcome.

Despite the small sample, our data resonate reports from the epidemic epicenter ³ , ⁴ , ¹¹ : Disease tends to be more severe among the KT population. Up‐to‐date, there has not been a single confirmed COVID‐19 case on a liver transplant (LT) alone recipient transplanted at the UAMS. If this is a random effect, whether it alludes to comorbidities inherent to the KT population or even a protective immunomodulatory effect on the LT population remains unclear. Notably, international studies have also shown a more indolent COVID‐19 course on the LT population. ¹⁷ , ¹⁸ It would be interesting to explore whether mild immunosuppression without T‐cell carpet‐bombing confers a shield against severe COVID‐19 elicited cytokine storm. ¹⁹ To be determined.

CONFLICT OF INTEREST

The authors of this manuscript have no conflicts of interest to disclose as described by Transplant Infectious Disease.

AUTHOR CONTRIBUTIONS

EG was responsible for conception, design, analysis and writing of the study; SZ, AS, SB, and LB were involved with the collection and interpretation of data, review and editing of the manuscript.