Pneumocystis jirovecii pneumonitis: cause of acute hypercalcaemia in chronic haemodialysis patient

Abstract

A 76-year-old renal transplant patient due to autosomal dominant polycystic kidney disease who resumed chronic haemodialysis was admitted to our hospital for confusion and lassitude. He was afebrile and physical examination revealed diffuse bilateral rales with decreased respiratory sounds in lower right lung. Laboratory data showed hypercalcaemia (total calcium 3.92 mmol/L (normal range 2.2–2.6 mmol/L), ionised calcium 1.87 mmol/L (1.15–1.35 mmol/L)), low intact parathyroid hormone (iPTH) 15 ng/L, (15–65 ng/L) and high 1,25(OH)2D3 128.9 pg/mL, (15.2–90.1 pg/mL). Chest CT-scan revealed bilateral apical lung lesions after 15 days of antibiotics. Bronchoalveolar sample was PCR positive for Pneumocystis jirovecii. He was treated with an extra session of haemodialysis with 1.25 mmol/L dialysate calcium concentration, oral trimethoprim-sulfamethoxazole was started and oral corticosteroid dose increased to 1 mg/kg for 1 week. Hypercalcaemia decreased progressively after initiation of these treatments. We concluded a case of hypercalcaemia secondary to P. jirovecii infection.

Background

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection which is generally observed in immunocompromised patients, especially those with AIDS.¹ Colonisation of the lower respiratory tract is very common,² but in patients with congenital or acquired immunodeficiency, it may cause severe lung infection with high morbidity and mortality.^{3 4} Kidney transplantation is among the main clinical settings associated with PJP.^{5 6} Nonetheless, the incidence of P. jirovecii has decreased with the worldwide recommendation of using antibiotic prophylaxis, but late infection can occur.^{7 8} Moreover, cases of hypercalcaemia associated with PJP have been reported in kidney transplant patients.^{9 10}

Here, we report a case of a haemodialysis patient who presented with hypercalcaemia secondary to PJP.

Case presentation

A 76-year-old patient underwent haemodialysis for 2.5 months after allograft failure before being admitted for confusion and lassitude.

Chronic haemodialysis was initiated in 1991 due to autosomal dominant polycystic kidney disease, before the patient received a deceased donor renal transplant in 1996. Initial immunosuppressive regimen was tacrolimus, mycophenolic acid (MPA) and prednisone.

In 2009, tacrolimus was discontinued because of evidence of calcineurin inhibitor toxicity in allograft biopsy. In 2013, he developed chronic antibody mediated rejection resulting in renewed haemodialysis in May 2018. On chronic haemodialysis, only low dose oral prednisolone was continued.

In July 2018, he presented with febrile state secondary to severe hypoxemic pneumonia confirmed by bilateral opacities in thoracic CT-scan (figure 1A). He was treated with ceftazidime and ofloxacine without microbiological documentation, but clinically improved and was discharged with oral prednisone 10 mg daily and the antibiotics continued for 15 days. Two weeks after this hospitalisation, he was admitted again because of confusion.

Figure 1.

(A) CHEST CT-scan performed 15 days before hospitalisation. Images showed bilateral diffuse peribronchovascular consolidative opacities with surrounding ground glass opacities. (B) Chest CT-scan performed during hospitalisation. Most of the peribronchovascular consolidative opacities had disappeared, but bilateral ground glass opacities remained.

At admission, he was afebrile and haemodynamically stable, but needed 2 L of oxygen to maintain oxygen saturation above 90%. Physical examination revealed diffuse bilateral rales with decreased respiratory sounds in lower right lung. Laboratory data showed hypercalcaemia (total calcium 3.92 mmol/L (normal range 2.2–2.6 mmol/L)), ionised calcium 1.87 mmol/L (1.15–1.35 mmol/L)), low intact parathyroid hormone (iPTH) 15 ng/L (15–65 ng/L), low bone alkaline phosphatase 9.7 µg/L (7.9–25.5 µg/L), high 1,25(OH)2D3 128.9 pg/mL (15.2–90.1 pg/mL) and elevated CRP (C reactive protein) 65 mg/L (<5 mg/L) with normal white cell count (8,78ˆx 10ˆ9/L (3,910–10,900 x 10ˆ9/L)) and low lymphocytes count (0.740 x 10ˆ9/L (1,500–4,000 x 10ˆ9/L)). Chronic dialysis sessions were performed with 1.5 mmol/L dialysate calcium. He was not on calcium or vitamin D derivatives supplementation in the last month before hospitalisation.

Investigations

The new chest CT-scan revealed persistent bilateral apical lung lesions after 15 days of antibiotics (figure 1B). In consequence, due to partial improvement of lung infection with antibiotics, continued low dose corticosteroid and his clinical background, the work up for atypical infections and systemic disease was performed.

QuantiFERON TB test was negative, but bronchoalveolar lavage sample demonstrated PCR positivity for P. jirovecii. All other microbiological samples were negative, including Mycobacterium tuberculosis. In addition, research for multiple myeloma was negative.

Treatment

To treat the hypercalcaemia and confusion, an urgent extra session of haemodialysis was performed with 1.25 mmol/L dialysate calcium.

PJP was treated with oral trimethoprim-sulfamethoxazole (TMP-SMX) 400/80 mg three times per day and oral corticosteroid dose increased to 1 mg/kg for 1 week.

Outcome and follow-up

Hypercalcaemia decreased progressively after initiation of antibiotics plus steroid and extra haemodialysis session. Clinically, the patient improved dramatically. Oxygen supplementation was stopped and confusion resolved 7 days after admission. He was discharged the following week on oral TMP-SMX for a total of 3 weeks (figure 2). In summary, we concluded a case of hypercalcaemia secondary to P. jirovecii infection.

Figure 2.

Patient follow-up. Serum levels of total calcium, ionised calcium, PTH, 1,25-dihydroxyvitamin D (1-25 OH vit. D), before, during and after treatment with trimethoprim-sulfamethoxazole. Only haemodialysis sessions performed during hospitalisation are shown. Left values are calcium level in mmol/L and right values are for iPTH and 1,25-dihydroxyvitamin D, in ng/L and pg/mL, respectively.

Discussion

Here, we report a case of hypercalcaemia induced confused state associated with PJP in a patient with history of renal transplantation resuming chronic haemodialysis 75 days before hospitalisation.

Hypercalcaemia in patients on renal replacement therapy without calcium and vitamin D supplementation is mainly due to hyperparathyroidism, even in kidney transplant recipients with functioning graft.¹¹ It is characterised by high plasma calcium level, high iPTH level and normal or low level of native and hydroxylated vitamin D. In our case, iPTH levels was very low and 1,25-dihydroxyvitamin D strongly increased. These biological findings suggest a granulomatous disease, like tuberculosis¹² or sarcoidosis.¹³ It may be explained by the extra renal production of 1,25-dihydroxyvitamin D by activated macrophages.¹⁴ Pathophysiology of hypercalcaemia in granulomatous disease is well known since 1987.¹⁵ In these case, 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitamin D in the granuloma without homoeostatic control because of the presence of 1α-hydroxylase enzyme (CYP27B1) in macrophages and giant cells, and leads to hypercalcaemia.

The first case of hypercalcaemia associated PJP in a kidney transplant recipient was described in 2002 by Chen et al ⁹ and reported by others later.^{10 16–20} Common characteristics of these cases were suppressed iPTH and increased 1,25-dihydroxyvitamin D, suggesting granulomatous disease.

In the literature, both microbial and non-infectious agents can lead to activation of extra-renal 1α-hydroxylase enzyme,²¹ but the most common are of infectious aetiology. Tuberculosis species is well known to induce hypercalcaemia with granulomatous reaction, but some case reports found various other microbial species. For example, a patient with AIDS complicated with Cryptococcus neoformans and Coccidioides immitis infections who developed hypercalcaemia with a high level of 1,25-dihydroxyvitamin D.²² Another case was a boy treated for acute lymphocytic leukaemia who developed hypercalcaemia a few months after disseminated candida infection.²³ A previous case-report summarised the biological effect of various fungal infections commonly associated with increased 1α-hydroxylase activity.²⁴ Furthermore, one case of malakoplakia induced hypercalcaemia was reported in the literature in which immunostaining for 25-hydroxyvitamin D3 and 1α-hydroxylase showed ectopic expression of enzymes in macrophages.²⁵ Other potential causes are foreign bodies like talc, silicone or inhalation of fat-like material and various immune diseases causing abnormal function of immune cells.²⁶

Th1 response is crucially involved in acute granuloma formation, by induction of M1 macrophages.^{27 28} M1 macrophages are involved in acute pathogen response. de la Rua et al, suggested in a mouse model that CD8+T cells upregulate (interferon-γ) IFN-γ responses during immune response to pneumocystis infection. The authors postulated that CD8+T cells enhance macrophage-mediated killing through the production of IFN-γ.²⁹ Induction of 1α-hydroxylase in antigen presenting cells takes place due to exposure to IFN-γ secreted via activated T lymphocytes.³⁰

Reciprocally, the effects of active vitamin D on the immune system are downregulation of costimulatory molecules CD28, CD86, CD40,³¹ a decrease of interleukin 2 (IL-2) and IL-12 and increase of IL-10 and induction of regulatory T cells. On the other hand, active vitamin D increases macrophage phagocytic activity, but blocks MHC (Major histocompatibility complex) class II expression and their maturation to antigen-presenting cells.^{32 33}

The other populations described in the literature presenting PJP-induced hypercalcaemia are paediatric, AIDS and leukaemic patients.^34–37 Interestingly, a common characteristic of these population is the immaturity or the dysfunction of lymphocyte T response, as in transplant recipients.²⁸

Our patient underwent several years of immunosuppressive therapy, notably MPA. This drug is an inhibitor of inosine-5'-monophosphate, targeting mainly T cells, but also B cells and monocytes.³⁸ B cells and monocytes are crucially involved in granuloma formation.²⁸

In our case, our hypothesis for development of PJP and 1,25-dihydroxyvitamin D-mediated hypercalcaemia is T cells dysfunction that persisted despite mycophenolate mofetil withdrawal more than 2 months before PJP infection.³⁸

In summary, we hypothesise that our patient presented with two major factors which could lead to granulomatous formation: first T cells abnormalities induced by immunosuppressive drug exposure and chronic kidney disease, especially haemodialysis³⁹; and second prolonged inflammatory state induced by P. jirovecii, leading to 1α-hydroxylase induction in macrophages and subsequent hypercalcaemia.

Learning points.

In conclusion, we present a case of a haemodialysis patient presenting with a Pneumocystis jirovecii pneumonia (PJP)-induced hypercalcaemia.

• We suggest increased awareness of acute hypercalcaemia in immunocompromised patients treated with dialysis after graft failure.

• As 1,25-dihydroxyvitamin D may be not part of routine evaluation, we think it must be requested promptly in cases of hypercalcaemia associated with suppressed iPTH and 25-hydroxyvitamin D.

• If 1,25-dihydroxyvitamin D is strongly elevated with suppressed level of iPTH, we suggest to work up for the causal microbial agents as the first step.