Adult purpura fulminans associated with staphylococcal infection and administration of colony-stimulating factors

ARTICLE

Purpura fulminans (PF) is an uncommon disorder characterized by the acute onset of skin necrosis and hemorrhagic changes due to dermal vascular thrombosis and disseminated intravascular coagulation (DIC). PF usually develops a few days after a relatively benign viral or bacterial infection or in conjunction with a severe infectious illness, particularly bacterial sepsis [1]. Most PF cases have been reported in children, although it can occur at all ages, and sometimes it represents a fatal disorder [2, 3]. In rare instances, PF appears to be secondary to drug intake [4].

We report a case of PF in an adult female with previous staphylococcal infection and pancytopenia of unknown origin, who developed skin and coagulation abnormalities after the administration of colony stimulating factors (CSF).

Case report

A 24-year-old female native of the province of Chubut (1400 km away from our Hospital) with no significant personal medical history presented fever and pharyngitis treated with acetyl salicylic acid 500 mg three times daily, loratadine 10 mg/day and cephalexine 4 g/day. Due to the persistence of fever and general condition worsening, laboratory studies and blood cultures were performed which showed pancytopenia (hematocrit 27 %, hemoglobin 9 g/dL; leukocyte 2,000 cells/mm³ with absolute neutrophil count of 100 cells/mm³; and platelets 86.500/mm³) and positive blood cultures for coagulase-negative Staphylococcus aureus. The patient was treated with sodic ampicillin 1 g/day and gentamicin 240 mg/day. The hematologist interpreted pancytopenia as drug-induced (no bone marrow aspiration was performed) and indicated G-CSF 300 mug/day i.m. Eleven days later, clinical improvement was noted but hematological abnormalities persisted, and G-CSF was switched to GM-CSF 300mug/day i.m. Forty eight hours later and after administration of two doses of GM-CSF, the patient presented fever (39.5 &sup0;C), bilateral and symmetric red-violet plaques in the upper and lower limbs, and breast. The lesions were painful. Blood examinations showed the presence of leukocytosis (12,500/mm³), anemia (hematocrit 26 %), thrombocytopenia (120,000/mm³) and coagulation abnormalities, with reduced fibrinogen (100 mg/ml) and prothrombin time (58 %), and increased INR (1.45) and kaolin partial thromboplastin time (KPTT, 49 sec). Skin lesions were interpreted as the result of vasculitis, and the patient was treated with prednisone 120 mg/day, amikacin 1 g/day and nadroparin 7500 IU every 12 hours, whereas GM-CSF was discontinued. Renal and liver function tests were normal. No skin biopsy was performed. As the clinical features were so dramatic, the patient was sent to our hospital for further investigation and treatment. On admission, she presented widespread red-violet plaques with geographical erythematous borders and purpura lesions, symmetrically distributed on the breast and four limbs. The back, buttocks, face, fingers and abdomen were not affected. The lesions rapidly evolved into necrotic-hemorragic blisters and necrotic eschars (Figs. 1, 2). Laboratory tests showed anemia, leukocytosis, thrombocytopenia and alteration in the coagulation parameters suggestive of DIC (Table I). Liver and renal function tests,
as well as rheumatology tests (ANA, lupus anticoagulant, anticardiolipin antibodies, complement fraction levels, cryoglobulins) were within normal limits, except reactive P-ANCA 1/320. Blood and skin cultures gave negative results. Skin biopsy specimens from the border of three different plaques showed diffuse dermal edema and vessel occlusion by fibrin thrombi (Fig. 3). Small vessels also showed some hemorrhagic areas with focal necrosis of their walls and erythrocyte extravasation. No inflammatory infiltrates were observed. The patient received metilprednisolone 100 mg/day. As the lesions remained clinically stable, surgical debridement of necrotic tissue followed by application of skin autografts taken from the patient's thighs was performed. Three months later the patient had completely recovered showing only residual scarring (Fig. 4).

Discussion

PF occurs predominantly in three clinical settings: (i) in neonates with congenital homozygous deficiency of protein C or protein S (neonatal PF); (ii) during a severe, acute infectious disease, usually due to Neisseria meningitidis sepsis, but occasionally caused by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae or other gram-negative bacteria, where a temporary C protein deficit can also occur (acute infectious PF); (iii) during the convalescent phase of an infection, more commonly streptococcal or a viral exanthema (postinfectious idiopathic PF), often associated with a temporary protein S deficit of autoimmune origin [1-4]. Regardless of the precipitating condition, PF presents initially with erythematous macules and petechiae, which rapidly evolve into painful, indurated and well-demarcated purpuric plaques. Late findings include hemorrhagic bullae, skin necrosis and eschars. Necrosis may extend to subcutaneous tissue, muscles and bones. Characteristic histopathologic feature is dermal vessel thrombosis. PF typically occurs in the setting of DIC. Vascular changes may be widespread and involve multiple organ systems, rendering PF a life-threatening disorder [1-4].

Diagnosis of PF in our patient was based on the presence of purpuric necrotic skin lesions, coagulation abnormalities consistent with DIC (elevated D-dimers, elevated fibrinogen degradation products, consumption of fibrinogen and platelets) and the presence of thrombi in dermal vessels with a previous record of staphylococcal infection. We cannot accurately determine whether this was an infectious PF or an idiopathic PF since neither protein C or protein S, nor anti-protein S antibodies dosage was performed. According to Frutos Martinez et al. [4], even though both protein S and protein C levels can be diminished in the context of DIC by consumption, antithrombin III, factors II and VII normal values suggest that protein S deficit is the crucial factor of the pathogenesis of idiopathic PF. This argument, together with the fact that our patient had been suffering from staphylococcal infection for 11 days with a favorable evolution, would support the diagnosis of idiopathic PF. In addition, the idiopathic variety is often confined to the skin, as in our case. We also want to stress the fact that the development of the lesions was very closely associated with the administration of CSFs. Indeed, drug intake has been indicated as a possible PF trigger [4]. In 1995, Mueller et al. reported the case of a child with HIV infection and DIC apparently caused by exposure to G-CSF [5]. They hypothesized that if granulopoiesis is stimulated on a long-term basis by G-CSF, it is possible that the disturbed maturation of these cells might lead to their disintegration in the marrow, thereby releasing thromboplastins, in a manner similar to the mechanism of DIC that commonly occurs during acute promyelocytic leukemia. In conclusion, although staphylococcal infection is probably involved in the aetiology of PF in our case, may be possible that CSF also played a role in the development of DIC associated with PF.

REFERENCES

1
Nolan J, Sinclair R. Review of management of purpura fulminans and two case reports. Br J Anaesth 2001; 86: 581-6.

2
Darmstadt GL. Acute infectious purpura fulminans: pathogenesis and medical management. Pediatr Dermatol 1998; 15: 169-83.

3
Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg M, Austen KF. Dermatology in General Medicine. Mc Graw Hill. 3^rd Ed., 1986, p. 2112.

4
Frutos Martinez C, Iturrioz Mata A, Gonzalez Perez-Yarza E, et al. Púrpura fulminante idiopática con déficit transitorio de proteína S An Esp Pediatr 2001; 55: 360-73.

5
Mueller BU, Burt R, Gulick L, et al. Disseminated intravascular coagulation associated with granulocyte- colony- stimulating factor therapy in a child with human immunodeficiency virus infection. J Pediatr 1995; 126: 749-52.