Co-infection with SARS-CoV-2 and Pneumocystis jirovecii in liver transplant recipients: A double whammy

Abbreviations

ACLF

Acute-on-Chronic-Liver Failure

AKI

Acute Kidney Injury

BAL

Bronchoalveolar Lavage

BDG

Beta-d-Glucan

CKD

Chronic Kidney Disease

CMV

Cytomegalovirus

CNI

Calcineurin Inhibitor

CT

Computed Tomography

CVVHDF

Continuous Veno-Venous Haemodiafiltration

HAT

Hepatic Artery Thrombus

HFNO

High Flow Nasal Oxygen

HRS-AKI

Hepatorenal Syndrome Acute Kidney Injury

ICU

Intensive Care

IgA

Immunoglobulin A

LDH

Lactate Dehydrogenase

LT

Liver Transplant

MMF

Mycophenolate Mofetil

PCP

Pneumocystis Pneumonia

PCR

polymerase chain reaction

P

jirovecii Pneumocystis jirovecii

PSC

Primary Sclerosing Cholangitis

SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

SOT

Solid Organ Transplant

TMP-SMX

Trimethoprim-Sulfamethoxazole

V-V ECMO

Veno-Venous Extracorporeal Membrane Oxygenation

Dear editor,We describe two cases of co-infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Pneumocystis jirovecii (P. jirovecii) in liver transplant (LT) recipients, causing coronavirus disease 19 (COVID-19) and pneumocystis pneumonia (PCP) respectively, during the second wave of the COVID-19 pandemic. Both patients became critically unwell and required intensive care (ICU) admission, with one receiving veno-venous extracorporeal membrane oxygenation (V-V ECMO) for 29 days for refractory type 1 respiratory failure (further clinical details are summarised in Table 1 ).

Table 1.

Patient characteristics at time of COVID-19 and PCP co-diagnosis and subsequent treatment.

	Case 1	Case 2
Age (years)	28	51
Indication for OLT	Decompensated AIH cirrhosis	Re-do OLT for HAT, initial OLT for PSC
Co-morbidities	T1DM, IgA deficiency, HRS-AKI at time of OLT requiring CVVHDF	CKD, UC (pan-proctocolectomy and ileostomy)
Time post OLT	1 month	8 years
COVID-19 vaccination	No	No
PCP prophylaxis	No	No
Immunosuppression at diagnosis	Basiliximab induction, tacrolimus (trough levels of 6–8μg/L), prednisolone (10 mg/day)	Tacrolimus (trough levels of 2–5μg/L), MMF (750 mg BD)
COVID-19 diagnosis	Positive nasopharyngeal swab PCR	Positive nasopharyngeal swab PCR
PCP diagnosis	Positive BAL PCR	Positive BAL PCR
CT thorax findings	Multifocal peripheral ground glass changes	Multifocal peripheral ground glass changes
BDG level (pg/ml)	266	227
WCC (x 109)	13.03	4.71
Lymphocyte count (x 109)	0.36	0.39
CRP (mg/L)	32	96
LDH (IU/L)	495	–
COVID-19 treatment	Dexamethasone (6 mg/day) escalated to methylprednisolone (1.5 mg/kg/day) plus remdesivir (200 mg loading then 100 mg/day for 4 days)	Prednisolone (40 mg/day)
PCP treatment	TMP-SMX, switched to primaquine and clindamycin due to pancytopaenia and methylprednisolone (1.5 mg/kg/day)	TMP-SMX, switched to primaquine and clindamycin due to pancytopaenia plus prednisolone (40 mg/day)
Immunosuppression changes	Prednisolone held whilst on IV steroids, low normal trough tacrolimus levels (5–7μg/L)	MMF held
ICU-specific treatment	Intubation and ventilation, V-V ECMO for 29 days, CVVHDF	Intubation and ventilation for 3 days, CVVHDF
3-month outcome	Remains in ICU	Remains in ICU

Abbreviations: AIH, autoimmune hepatitis; BAL, bronchoalveolar lavage; BD, twice daily; BDG, beta-D glucan; CRP, C-reactive protein; CKD, chronic kidney disease; COVID 19, coronavirus disease 19; CT, computed tomography; CVVHDF, continuous veno-venous haemodiafiltration; HAT, hepatic artery thrombus; HRS-AKI, hepatorenal syndrome acute kidney injury; ICU, intensive care unit; IgA, immunoglobulin A; IV, intravenous; LDH, lactate dehydrogenase; MMF, mycophenolate mofetil; OLT, orthotopic liver transplantation; PCP, pneumocystis pneumonia; PCR, polymerase chain reaction; PSC, primary sclerosing cholangitis; T1DM, type 1 diabetes mellitus; TMP-SMX, trimethoprim-sulfamethoxazole; UC, ulcerative colitis; VV-ECMO, veno-venous extracorporeal membrane oxygenation; WCC, white cell count.

P. jirovecii is an opportunistic fungus that causes PCP in the immunocompromised, including solid organ transplant (SOT) recipients, and carries a high morbidity and mortality. Studies have suggested it occurs in less than 3% of LT recipients not receiving prophylaxis [1]. In the absence of prophylaxis, PCP risk is highest in the first 6-months post transplantation. Other risks factors include cytomegalovirus (CMV) infection, hypogammaglobulinaemia, lymphopenia, treated graft rejection and increasing age [2].

We report the first two documented cases of concurrent severe COVID-19 and PCP in LT recipients. There are several case reports in the literature describing co-infection in immunocompromised patients, such as those with HIV [3]. One of our cases had multiple risk factors for P. jirovecii infection, including timing post-transplant and hypogammaglobulinaemia, and the other was on an anti-metabolite. Whilst both patients have survived 3-months post diagnosis, they remain in ICU, highlighting the grave morbidity associated with severe COVID-19 and PCP co-infection.

Severe COVID-19 and PCP share many clinical characteristics, including profound hypoxaemia and bilateral pulmonary infiltrates on imaging, creating a diagnostic dilemma. A raised beta-D glucan (BDG) and serum lactate dehydrogenase (LDH) should raise suspicion for concurrent PCP [2]. Whilst COVID-19 testing is now readily available via nasopharyngeal swab PCR, PCP is notoriously difficult to diagnose, and gold standard remains via bronchoalveolar lavage (BAL) fluid. The use of steroids in the treatment of severe COVID-19 may further delay PCP diagnosis, due to their favourable effect on PCP leading to transient clinical improvement [3].

Lymphocyte count at time of concurrent PCP diagnosis was 0.36 × 10⁹/L and 0.39 × 10⁹/L in our patients. Lymphopenia is common in SARS-CoV-2 infection [4], and CD4⁺T lymphocytes play a crucial role in the immune response against P. jirovecii [2]. SARS-CoV-2 infection may result in a further functional immune suppression in already immunocompromised LT recipients, increasing the risk of P. jirovecii infection.

The incidence and outcome of COVID-19 in LT recipients remain a matter of debate. Nonetheless, vaccination in this patient group is of paramount importance. However, SOT recipients are at risk for lower vaccine immunogenicity, due to impaired immune response, and were excluded from clinical trials. Recent real-world data has revealed lower immunological response, with both reduced serological antibody production (SARS-CoV-2 IgG antibodies against Spike-protein (S)) and antibody titre, amongst LT patients to the BNT162b2 vaccine [5].

We highlight the importance of a high index of suspicion for co-infection with SARS-CoV-2 and P. jirovecii in LT recipients. Additional investigations, such as serum LDH, BDG and ultimately BAL, should be considered. With the continuing pandemic, and reduced level of protection vaccination offers LT recipients, co-infection with PCP requires attention. Should further data on co-infection be reported, PCP prophylaxis in LT patients with severe COVID-19, especially with other risk factors, may require consideration given our experience of significant morbidity in this patient cohort.

Conflicts of Interest

The authors of this manuscript have no conflicts of interest to disclose. K.A. was sub-investigator in the Gilead Remdesivir and RECOVERY trial. KA is P.I. of the MK-4482-002 trial (Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19).