Klebsiella‐induced acute infectious purpura fulminans in a Thai woman: Case report and review of literature

Abstract Purpura fulminans (PF) is an uncommon syndrome of acute purplish skin eruption characterized by coagulation of the microvasculature, which leads to purplish lesions and skin necrosis. There are three subtypes; idiopathic PF, neonatal PF and, the most common subtype, acute infectious PF (AIPF). Acute infectious PF is related to the thrombotic subtype of disseminated intravascular coagulation (DIC) and usually is superimposed on sepsis. This can rapidly lead to multi‐organ failure from thrombotic occlusion of small and medium‐sized blood vessels. We report a case of Klebsiella‐induced AIPF in a 78‐year‐old Thai woman and also review other published cases.


| CASE REPORT
A 78-year-old Thai woman was admitted to our department due to pneumonia with sepsis. She was brought to the intensive care unit due to shock and multi-organ failure, requiring the use of mechanical ventilation and vasopressors. She was prescribed cefoperazone with sulbactam (sulperazone) and colistin.
On the third day of hospitalisation, physical examination revealed cold bilateral distal extremities and skin mottling in the left lower extremity. The skin mottling progressed, eventually resulting in a purpuric rash and bullae across the left lower leg [ Figures 1 and 2]. Dermatology consultation was requested on the fifth day to confirm the clinical suspicion of acute infectious PF (AIPF). A biopsy was performed. Laboratory testing showed anaemia, thrombocytopaenia, a high prothrombin, time (PT)/partial, thromboplastin time (PTT) ratio [prolonged PT (24. At the time of presentation, two further differential diagnoses were considered: vasopressor-induced necrosis and PF. Given her gangrenous left lower extremity, vasopressor-induced necrosis was a possibility, but it was ruled out due to the haemorrhagic bullae development early on, fast progression to her lower extremities, and laboratory abnormalities indicative of DIC.
Microscopic examination revealed confluent necrosis of the overlying epidermis, with a subepidermal vesicle that contained a few lymphocytes. The dermis showed a perivascular and interstitial mixed inflammatory cell infiltrate composed of lymphocytes and a few neutrophils in the dermis and subcutaneous tissue. Fibrin thrombi were seen in many small to medium-sized blood vessels. The pathological diagnosis was epidermal necrosis with fibrin thrombi [ Figure 3 -6].
Sputum cultures indicated positive growth for Klebsiella pneumoniae 2 days after pathology findings were reported, and blood cultures (VITEK 2 system) confirmed positive growth for Klebsiella pneumoniae sensitive to sulperazone and colistin.
One week after empirical antibiotic treatment, sepsis and AIPF improved.
Based on a case of rapidly progressing retiform purpura, DIC, skin biopsy findings, and clinical improvement after antibiotic therapy, the most likely diagnosis in our patient was PF associated to Klebsiella pneumoniae sepsis.

| DISCUSSION
Purpura fulminans is an uncommon syndrome of acute purplish skin eruption characterised by DIC, failure of the circulation and dermal vascular thrombosis, which leads to cutaneous haemorrhagic purplish lesions and skin necrosis in the trunk and extremities. [1][2][3][4][5] PF is a life-threatening disorder with a mortality rate up to 60%. 1,6 Idiopathic PF, neonatal PF and AIPF are the three subtypes. 2,7 The most prevalent subtype is AIPF which occurs in conjunction with sepsis and is linked to the thrombotic subtype of DIC.
This syndrome has significant death rate and is mostly seen in children, with only 4% of cases affected patients over the age of twelve. 8 Fever, shock and systemic consumptive coagulopathy occur in affected patients, leading to multisystem organ failure, 9 with Waterhouse-Friderichsen syndrome (DIC, organ failure, and adrenal haemorrhage) as the leading cause of mortality. 10 The most common infectious aetiologies are Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, although other species have also been implicated, as in Table 1. 1,4,[11][12][13][14][15] Amidst COVID 19 ongoing pandemic, incidences of AIPF from SARS-CoV-2 have been reported as a manifestation of COVID-19. 14,15 Acute infectious PF results from the crosstalk between the septic and coagulation cascades. Attenuation of thrombomodulin (TM), a cofactor of thrombin that activates protein C (PC) and plays a role in endogenous anticoagulation, is caused by the underlying infection. 3 A lack of TM inhibits PC activation, allowing coagulation to proceed uncontrolled, which results in DIC. 16 Two potential pathways for the decrease of TM function in response to infections have been postulated by in vitro investigations. While a few studies have shown that infections cause downregulation of TM gene activity, other recent researches suggest that the protein is cleaved from the endothelium surface via a posttranscriptional process, leading to the loss of coagulation negative feedback loop. [16][17][18] Patients with PF initially present with erythematous macules that quickly become indurated, non-blanching petechiae, leading to ecchymoses and purpuric plaques on the trunk and extremities. 1 Early lesions may resemble a livedo pattern with mottled skin. 1 The most T A B L E 1 Aetiologies of Purpura fulminans (PF) 1,4,14 Organisms/Conditions  characteristic cutaneous finding of PF is diffused, noninflammatory retiform purpura from extensive microvascular occlusion. 19 Bullae secondary to skin necrosis may be seen. 12 Patients may present with ischaemic digits, extremities 3,20 or symmetrical peripheral gangrene which is characterized by symmetrical distal gangrene in absence of any large vessel occlusion and it is usually associated with critical illness. 14 In cases of DIC, more severe phenotypes can be encountered such as symmetrical necrotic purpura, haemorrhagic bullae and/or widespread ecchymoses and epidermal necrosis. 5 If left untreated, AIPF can progress to symmetrical peripheral gangrene, digital and/or limb amputations and end-organ failure. This pattern rapidly develops into permanent full-thickness necrosis of the skin within 24-48 h, as opposed to purpuric rashes found in other diseases, including immune thrombocytopenic purpura or thrombotic thrombocytopaenia purpura. Patients with AIPF may also be vulnerable to secondary infection. 1,4,21 Prolonged plasma clotting times, thrombocytopaenia, decreased plasma fibrinogen concentration, increased plasma fibrin-degradation products and microangiopathic haemolysis are all common laboratory findings in patients with PF. 1,4 This pattern of abnormalities, however, is not diagnostic of PF and may occur in DIC from other causes. 4 In addition, Patients with PF often have high C-reactive protein (CRP) levels while their erythrocyte sedimentation rate (ESR) is abnormally low. 1 This "ESR-CRP disassociation" is caused by relative or absolute hypofibrinogenaemia in the presence of DIC, resulting in a depressed ESR. 1 PC and protein S levels are typically lower in PF patients. [22][23][24] PC levels of less than 40% are especially indicative of PF. 23 Table 2 shows the clinical and laboratory characteristics of PF. 1 Histopathologically, there is dermal vascular thrombosis with the presence of mixed microthrombi composed of fibrin, platelets, and leucocytes in the dermal blood vessels. 1,3,8,9 Microthrombi of tiny cutaneous arteries correspond histologically with the first clinical symptoms. 1 Endothelial cell enlargement and capillary dilatation then follow, leading to cell separation and blood vessel rupture with bleeding into the dermal stroma. 3 The characteristic presence of a perivascular neutrophilic infiltration differentiates AIPF from both postinfectious (idiopathic) and haemostasis-induced (neonatal) PF. 12 Despite improvement in our knowledge of the processes causing PF, clinical judgement is still required when diagnosing patients and recommending therapy. In the case of AIPF, antibiotic medication is used in conjunction with supportive care. There is currently no agreement on how to treat PF. Broad-spectrum antibiotics, anti-coagulants, PC concentrate, platelets and fresh frozen plasma (FFP) are some of the therapies that have been used. 1,4-7 PF patients with DIC need immediate FFP (10-20 ml/kg every 8-12 h) to replenish procoagulant and anti-coagulant plasma proteins lost during DIC. AIFP cases with significant thrombocytopaenia (platelet count <50 � 10 9 /dl) and hypofibrinogenaemia (fibrinogen concentration <1 g/dl) may need additional platelet concentrates (10-15 ml/kg) or cryoprecipitate transfusions (5 ml/kg), especially if pathological bleeding is also present. At present, therapies focus on therapeutic anticoagulation and rapid replenishment of circulating antithrombotic proteins, while future treatments may leverage the cytoprotective benefits of the PC pathway in addition to the current standard of care. 16 Because of rapid and severe disease progression, it is imperative for clinicians to provide correct diagnosis and treatment of PF. Warfarin-induced skin necrosis, cryoglobulinaemic vasculitis, anti-phospholipid syndrome, heparin-induced thrombocytopaenia, meningococcal infection and Henoch-Schönlein purpura are among the differential diagnoses. 1 Infectious PF is an uncommon but deadly condition characterised by a thrombotic type of DIC, haemodynamic collapse, and haemorrhagic cutaneous necrosis. A delay in diagnosis can have serious clinical repercussions for the patient, including amputation of limbs and death. Despite advances in our knowledge of the processes behind PF, clinical judgement is still required when diagnosing patients and in recommending therapy. In conclusion, we described a rare unique case of an adult with Klebsiella-induced AIPF. This case highlights the significance of evaluating PF in adults with sepsis. Only eight cases of PF have been reported in the setting of Klebsiella spp infection since 2002, four being K. pneumoniae and two of Klebsiella oxytoca and one of Klebsiella rhinoscleromatis (Table 3). [Correction added on 24-November-2022, after first online publication: the number of cases was changed from six to eight in the preceding sentence.] Our case is the fourth case of Klebsiella pneumoniae-induced AIPF, in which prompt antibiotic treatment and intensive care therapy are critical for the patient's survival. Only one out of four case reports was a neonate, whereas the rest happened in adult patients.

CONFLICT OF INTEREST
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

DATA AVAILABILITY STATEMENT
Data available on request due to privacy/ethical restriction.

ETHICS STATEMENT
Not applicable.