Citrobacter freundii sepsis in an immunosuppressed patient with pemphigus vulgaris

Abstract

Pemphigus vulgaris is an autoimmune bullous disease that involves the skin and mucous membranes. Current therapies aim to decrease antibody production by means of the use of systemic corticosteroids, immunosuppressive agents and, recently, rituximab, an anti-CD20 monoclonal antibody. However, the chronic immune suppression could entail complications, like infections and secondary malignancies. We describe a case of a patient with pemphigus who developed a sepsis due to Citrobacter freundii infection.

Background

Pemphigus vulgaris is an autoimmune blistering disease affecting the skin and mucous membranes, produced by autoantibodies targeting the desmosomal structural proteins (desmoglein 1 and desmoglein 3), which mediate adhesion between keratinocytes, resulting in intraepidermal acantholysis and blister formation. Current therapy of pemphigus is based on anti-inflammatory and immunosuppressive agents in order to decrease tissue inflammation and reduce antibody production.¹ Rituximab, a chimeric monoclonal antibody against CD20 antigen of B lymphocytes, proved to be effective in resistant and severe pemphigus forms.² Because of its immunosuppressive effect, rituximab increases the risk of infectious complication depletion on peripheral blood B cells for variable time periods (typically 6–9 months).³ Most infections are rarely fatal and generally involve upper respiratory tract.⁴ Citrobacter spp are facultative anaerobic Gram-negative bacilli within the family Enterobacteriaceae, found as normal inhabitants of the intestinal tract of humans. The most frequent species are C. amalonaticus, C. koseri (C. diversus) and C. freundii, often hospital acquired and responsible for sepsis or severe visceral opportunistic infections in newborns, older patients and immunocompromised hosts. Generally, the sepsis originates from tissue injuries or inflammation at the site of colonisation (gastrointestinal tract, wounds and decubitus ulcers).^5–7

Case presentation

We present a case of a 66-year-old man followed in our dermatologic unit for 6 years with pemphigus vulgaris, involving scalp, trunk and oral mucosa. His medical history revealed only Hashimoto thyroiditis in replacement treatment. He also underwent an appendectomy (at the age of 16) and a hospitalisation for pneumonia (at the age of 32). At diagnosis, the patient was initially treated with high-dose systemic corticosteroids, subsequently associated with plasmapheresis (two sessions/week) and azathioprine 100 mg/day. Two years ago, following a worsening of the clinical conditions, the patient underwent an infusion of rituximab 500 mg at 2 weeks interval with partial improvement of the symptomatology. Recently, the patient experienced another relapse with worsening of both skin and oral mucosal lesions, resulting in the inability to eat solids. Due to the lack of response to conventional immunosuppressive therapies including steroids and azathioprine, we decided to administer rituximab using a single ultralow-dose regimen of 200 mg. The choice of this therapeutic regimen was determined by the immunocompromised condition of the patient in order to decrease the risk of potential infectious complications. After 1 month from the infusion, given the persistence of the lesions, we decided to hospitalise the patient for further investigations and to evaluate the possibility of a cycle of plasmapheresis. After 4 days of hospitalisation, the patient underwent a febrile peak with a maximum of 41°C accompanied by hypotension (blood pressure 85/55 mm Hg). The patient was then treated with antifungal therapy (fluconazole 600 mg/day and then 400 mg/day), broad-spectrum antibiotic (piperacillin and tazobactam 4.5 mg four times a day+levofloxacin 750 mg/day) and infusions of plasma expanders for haemodynamic support. Routine blood tests showed leukophilia (18.9×10⁹/L) with neutrophilia (11.98×10⁹/L), thrombocytopenia (105×10⁹/L), increase in C-reactive protein (44.3 mg/L) and procalcitonin (11.37 μg/L), and coagulation alterations. A chest X-ray showed no signs of pathology. Microbiological investigations demonstrated that urine culture was negative whereas blood culture was positive for Gram-negative rods. On the second day, C-reactive protein was 140 mg/L and procalcitonin 64.5 μg/L. In the following days, Gram-negative rods were confirmed by the blood culture results and this microorganism was promptly identified as Citrobacter freundii. Antibiogram revealed the following minimum inhibitory concentrations: amoxicillin/clavulanic acid 8 µg/mL (resistant), cefotaxime ≤1 µg/mL (sensitive), ceftazidime ≤1 µg/mL (sensitive), cefepime ≤1 µg/mL (sensitive), meropenem ≤0.25 µg/mL (sensitive), imipenem ≤0.25 µg/mL (sensitive), trimethoprim/sulfamethoxazole <0.25 µg/mL (sensitive), ciprofloxacin ≤0.25 µg/mL (sensitive), gentamicin ≤1 µg/mL (sensitive), amikacin ≤2 µg/mL (sensitive) and piperacillin/tazobactam ≤4 µg/mL (sensitive).

Outcome and follow-up

Based on the results of blood culture and antibiogram, antibiotic therapy was modified with the introduction of ceftriaxone 2 g/day for 10 days as susceptibility to cefotaxime can be used to predict susceptibility to ceftriaxone within the Enterobacteriaceae. Clinical conditions of the patient slowly improved with stabilisation of the haemodynamic parameters and decrease in body temperature. At present, the patient is in good health and complete remission.

Discussion

Citrobacter spp, especially C. freundii and C. koseri, are significant pathogens in patients with underlying diseases or an immunocompromised status. They are often hospital acquired and could cause sepsis or severe visceral opportunistic infections. In adults, the sources of bloodstream infections are, generally, the abdominal cavity, the urinary tract, the respiratory system or intravascular catheters. Rarely skin and soft tissue are involved.^5–7 Only a few cases of sepsis from C. freundii infections have been reported in the literature. C. freundii bacteraemia mostly occurs in immunocompromised individuals, notably elderly patients affected by systemic diseases like cancers and lymphoproliferative disorders or patients under treatment with dialysis or immunosuppressive therapies.^{7 8} Cases of Citrobacter infections in immunocompetent patients are rare and involve predominantly urinary and respiratory tracts.⁹ In our case, the sepsis from C. freundii occurred in an immunocompromised patient following chronic immunosuppressive therapy. This is the first case reported in the literature and indicates that patients under long-term immunosuppression may have a higher risk of infectious complications. In this case, we used a single ultralow dose of rituximab (200 mg) to decrease the risk of serious infections maintaining the effectiveness of the traditional dosage. The optimal dosage of rituximab for treatment of pemphigus has not been clearly defined. Initially the most used regimen was the lymphoma protocol (375 mg/week for 4 weeks), nowadays some centres prefer two doses of 1000 mg given 2 weeks apart or 500 mg at 2 weeks interval because of the better side effect profile.¹⁰ In our experience, we observed the persistent suppression of B cell count for several months after a single very low dose of rituximab (200 mg).¹¹ Moreover, a recent study demonstrated that less than 1% of the conventional rituximab dose induced a nearly complete depletion of circulating B lymphocytes in healthy volunteers.^{12 13}

In conclusion, this case shows that the chronic immunosuppression used for the treatment of pemphigus could cause severe infections, potentially fatal. Further studies are needed in order to find the optimal effective immunosuppressive regimen that may allow to minimise the occurrence of the infectious complications. This case underlines the necessity in this autoimmune blistering condition to find a balance between the risks related to the chronic immunosuppressive therapy and those related to the pathology itself.

Learning points.

• The chronic immunosuppressive regimen used in pemphigus may be associated with an increased risk of infectious complications that should not be underestimated.

• Citrobacterfreundii is a Gram-negative bacterium, found as normal inhabitant of the intestinal tract, and potentially associated with septic states in immunocompromised patients.

• There is the necessity in the treatment of pemphigus to find a balance between the risks related to the chronic immunosuppressive therapy and those related to the pathology itself.