Acute infectious purpura fulminans: a case series from India

Introduction

Purpura fulminans is characterised by coagulation of the microvasculature presenting with an acute purpuric rash and skin necrosis. Patients often present with fever and features of sepsis and shock requiring rapid diagnosis and management. Affecting all age groups, it is often complicated by disseminated intravascular coagulation. Despite advances in diagnostic modalities, the condition continues to have a high mortality and morbidity.

Materials and methods

Our study was carried out in a tertiary care centre in Southern India between March 2005 and March 2017. All patients aged ≥18 years admitted with acute febrile illness and purpura fulminans were included in the study; however, cases secondary to autoimmune and malignant aetiology were excluded. Data regarding patient demographics, clinical characteristics, laboratory and radiological parameters, treatment and outcomes were reviewed. Continuous variables were summarised using mean and standard deviation (SD) when normally distributed and median and interquartile range (IQR) when not normally distributed. Categorical variables were analysed using proportions. The study was approved by the Institutional Review Board and Ethics Committee ((IRB Min No. 10730 (retro) dated 21 June 2017). Data were analysed using SPSS v20. (IBM Corp., Armonk, NY, USA).

Results

A total of 11 patients (seven male) were found; four were diabetic and one was pregnant, one proved HIV positive and one more hypertensive. The most common symptoms at presentation were fever (100%), confusion (63.6%) and headache (55%), and the most common laboratory abnormalities were thrombocytopenia (100%), elevated alkaline phosphatase (70%) and anaemia (63.6%). Acute kidney injury was seen in 5 (45.6%) patients, gangrene in 3 (27%) patients and shock in 2 (18%) patients.

Baseline characteristics are summarised in Table 1. Of the 2 patients with Neisseria meningitidis infection, one had grown the organism in culture and the other was confirmed by latex agglutination and polymerase chain reaction in CSF. Five had serology confirmed spotted fever group rickettsioses (SFG.) One patient had Aeromonas sepsis and one 27-year-old man who survived had fever positive Dengue IgM.

OPEN IN VIEWER

Table 1.

Clinical characteristics.

Parameter
Total	11 (100)
Age (years)	39.8 ± 17.7
Men	7 (63.6)
Diabetes mellitus	4 (36.3)
Fever	11 (100)
Headache	6 (55)
Vomiting	2 (18.2)
Confusion/unresponsiveness	7 (63.6)
Abdominal pain	2 (18.2)
Diarrhoea	2 (18.2)
Shock	2 (18.2)
Gangrene	3 (27)
Case fatality	2 (18.2)
Hospital stay (days)	10.2 ± 5.5
Haemoglobin (g/dL)	12.4 ± 3.2
WBC count (×103/mm3)	17.8 ± 8.5
Platelet count (×103/mm3)	59.5 ± 42.5
Serum creatinine (mg/dL)	1.4 ± 0.7
Elevated transaminases (threefold rise in levels)	3/10 (30)
Elevated alkaline phosphatase (>125 IU)	7/10 (70)
Deranged PT/aPTT	5/10 (50)

All 11 patients received broad spectrum antibiotics: cephalosporins (n = 8); piperacilin tazobactam (n = 2); and ciprofloxacin with metronidazole (1). Nine patients also had doxycycline or azithromycin for Rickettsial infection (Table 2). Six patients (55%) required admission to the intensive care unit (ICU), on account of the need for mechanical or non-invasive ventilation, inotropic support or haemodialysis. The mean hospital stay was 10.2 days. Overall mortality was 2 (18.2%). One patient left against medical advice.

OPEN IN VIEWER

Table 2.

Risk factors, diagnosis, treatment received and outcomes in all the patients with purpura fulminans.

Age/ Gender	Clinical presentation	Co-morbid conditions	Organism identified in culture/PCR	Rickettsial serology	ANA	Other diagnostic tests	Antibiotics received	Skin biopsy	Patient outcome (cause of death)
18/M	Fever, confusion, headache		Neisseria meningitidis (CSF culture)	Negative	Not done		Ceftriaxone, Aciclovir	Not done	Death (multi-organ dysfunction and DIC)
65/F	Fever, confusion, headache, abdominal pain	HIV infection, hypertension	Negative	Negative	Negative	Antibodies to beta 2 glycoprotein, lupus anticoagulant and anticardiolipin antibody – negative	Ceftriaxone, doxycycline	Not done	Alive
35/F	Fever		Aeromonas hydrophila (blood culture)	Not done	Not done		Ciprofloxacin, metronidazole	Not done	DAMA
27/M	Fever		Negative	Negative	Negative	Dengue IgM – positive	Ceftriaxone, doxycycline	Not done	Alive
56/M	Fever, confusion, headache, peripheral gangrene	Diabetes	Negative	Weil Felix OX 2 – positive	Not done		Cefotaxime, doxycycline	Not done	Alive
54/M	Fever	Diabetes	Negative	Spotted fever IgM and IgG positive	Negative		Ceftriaxone, doxycycline	Epidermal necrosis and small vessel neutrophilic vasculitis	Alive
55/F	Fever, confusion, shock	Diabetes	Negative	Spotted fever IgM and IgG positive	Positive – Speckled 1+		Piperacillin-tazobactam, doxycycline, azithromycin	Dermal capillary thrombosis	Alive
54/M	Fever, abdominal pain, diarrhoea, vomiting, shock, peripheral gangrene	Diabetes	Negative	Weil Felix OX 2 – positive	Not done		Piperacillin-tazobactam, doxycycline, azithromycin	Not done	Death (multi-organ dysfunction)
18/M	Fever, confusion, headache, peripheral gangrene		Negative	Negative	Negative		Ceftriaxone, doxycycline	Coagulopathic reaction with sweat gland necrosis	Alive
22/F	Fever, confusion, headache	Pregnancy	Negative	Spotted fever IgM positive	Positive – speckled 1+		Ceftriaxone, azithromycin	Not done	Alive
37/M	Fever, confusion, headache, diarrhoea, vomiting	Alcohol excess	Neisseria meningitidis (latex agglutination and PCR in CSF)	Negative	Not done		Ceftriaxone, vancomycin, doxycycline	Coagulopathic reaction	Alive

Discussion

Based on the triggering factor, purpura fulminans can be classified into three forms, namely neonatal purpura fulminans, idiopathic purpura fulminans and acute infectious purpura fulminans. ¹ While neonatal purpura fulminans is due to inherited deficiency of protein C or protein S and presents within 72 h of birth, idiopathic purpura fulminans follows 7–10 days of an acute viral or bacterial illness and is due to transient decrease in protein C or protein S or antithrombin III levels.

The most common form of acute infectious purpura fulminans occurs in conjunction with a bacterial or a Rickettsial infection. The bacterial endotoxin disturbs the balance of anticoagulant and procoagulant activity of the endothelium resulting in transient reduction of protein C, protein S or antithrombin III levels. ²

The key finding from our study is that in the tropics, the most common cause is not meningococcal bacteraemia but SFG rickettsiosis. In India, this is caused by tick-borne Rickettsia rickettsiae, Rickettsia conorii or the mite-borne Rickettsia akari. ³ Transmitted by the vectors through the skin into the lymphatics and blood, the ricketssiae attach to and enter the vascular endothelium and vascular smooth muscle cells by means of a surface-exposed protein and rickettsial phospholipase. Within, they invade, multiply and are directly cytopathic, producing a generalised vascular injury, leading to activation of clotting factors, extravasation of fluid and tissue hypoperfusion. ⁴ Peripheral digital gangrene seen in three of our series is secondary to thrombosis. No anticoagulation is recommended.

The rash in spotted fever begins after 2–3 days of illness as a blanching macule, 1–4 mm in diameter, and later becomes petechial. It begins on the ankles and wrists and then involves the trunk, palms and soles. In severe cases, the rash becomes confluent and may progress to necrosis. ⁵

Purpura fulminans in children secondary to Rickettsial infection has been reported in India.^6–10

The presence of a typical Rickettsial rash is helpful in making a presumptive diagnosis of SFG rickettsioses. ¹¹ However, the diagnosis should be confirmed by either the Weil Felix test or, preferably, IgG and IgM ELISA for antibodies. Hepatic and renal monitoring is advisable. Definitive treatment is with azithromycin 500 mg o.d. for five days or doxycycline 100 mg b.d. for seven days.

In India, the prevalence of meningococcal disease is low and usually occurs in epidemics. ¹² Purpura fulminans occurs in 15%–25% of patients with meningococcemia and carries a high mortality. ¹³ Empirical treatment in cases of purpura fulminans should nonetheless continue to include treatment for meningococcal disease until a microbiological diagnosis is made. A lumbar puncture is only indicated where there is clinical evidence of meningitis and not in all patients with purpura fulminans.

In published literature, we found only one case of Aeromonas sepsis complicated by purpura fulminans – a 12-year old boy with aplastic anaemia, dying despite antimicrobial therapy, ¹⁴ and only one case of Dengue fever complicated by purpura fulminans. ¹⁵

An obvious limitation in our study is its retrospective nature including patients from only one centre.

Conclusion

Purpura fulminans has a high morbidity and mortality. All patients presenting with an acute febrile illness and purpura fulminans should be empirically treated for both meningococcal disease and spotted fever rickettsioses until a definite microbiological diagnosis is established.