Non-typeable Haemophilus influenzae and purpura fulminans

Abstract

Haemophilus influenzae typically causes illness and infection in the paediatric population. We report a case of a 53-year-old man who developed invasive non-typeable H. influenzae infection associated with purpura fulminans and multiorgan failure. On review of the literature, this is the first reported case of non-typeable H. influenzae causing purpura fulminans. The patient was treated with intravenous ceftriaxone 2 g/day and was eventually discharged from the hospital almost 2 months after admission. We discuss the role that infection/sepsis plays in disturbances to the coagulation cascade leading to purpura fulminans and the virulence factors that make non-typeable H. influenzae unique. Finally, we review other cases of H. influenzae associated with purpura fulminans and discuss the similarities with our case.

Background

Haemophilus influenzae is a Gram-negative coccobacillus that inhabits the human upper respiratory tract. There are several serotypes of H. influenzae, the most common being the type b (Hib). The various serotypes, a through f, are distinguished from each other by the type of capsule and are distinct from the non-typeable H. influenzae which has no capsule. The advent and widespread use of the conjugate vaccine to Hib has altered the incidence of the serotype causing illness in developed countries.^{1 2} The non-typeable H. influenzae is usually implicated in otitis media, exacerbations of chronic obstructive pulmonary disease and community-acquired pneumonia and is now more prevalent than encapsulated H. influenzae. However, non-typeable H. influenzae has also been known to cause bacteraemia and severe sepsis, particularly in those with an immunocompromising condition.²

Purpura fulminans is a skin condition characterised by purpuric lesions and skin necrosis and is usually a heralding sign of organ failure. It can be due to both haematological and infectious causes, particularly sepsis. Sepsis causes alterations in the coagulation cascade and can trigger disseminated intravascular coagulation (DIC) leading to thrombosis of the vascular supply of the skin. Treatment typically involves addressing the underlying condition as well as meticulous skin care given that the purpuric lesions themselves can be secondarily infected leading to gangrene.³

We present the first reported case in the literature of purpura fulminans caused by non-typeable H. influenzae in an adult.

Case presentation

A 53-year-old man with a previous medical history of type 1 diabetes mellitus, hypothyroidism and hypertension presented with altered mental status after being found down by his roommate. During the week prior to his presentation, the patient had flu-like symptoms: fever, chills and myalgias with associated symptoms of nausea and vomiting. As per the patient’s roommate, he was unconscious for at least 3 hours prior to being transported to the hospital. His medications included insulin lispro and over the counter vitamins. He worked as a private security officer and was previously a policeman. He was sexually active with men, drank on the weekends and smoked half a pack of cigarettes a day. On initial examination, the patient’s temperature was 32.9°C (91.2°F), heart rate was 79 beats/min, blood pressure was 74/49 mm Hg, respiratory rate was 26 breaths/min and he had an SpO₂% of 100% on room air. He was unconscious, unresponsive to sternal rub and his eye examination revealed anisocoria with a 4 mm right pupil and a 3 mm left pupil, neither responsive to light. His skin examination was significant for sharply demarcated retiform purpura and necrosis of the right shoulder, right upper chest, right dorsal foot, with isolated bullae in the right antecubital fossa surrounding his intravenous site (figures 1–3).

Figure 1.

Picture demonstrating the appearance of purpura fulminans and haemorrhagic bullae near the patient’s intravenous site at the right antecubital fossa.

Figure 2.

Picture demonstrating the extent of the purpura fulminans near the patient’s intravenous site at the right antecubital fossa.

Figure 3.

Picture demonstrating the extent of the purpura fulminans across the patient’s right shoulder and upper back.

Investigations

His electrolytes showed a sodium of 115 mmol/L (135–145 mmol/L), potassium of 7.3 mmol/L (3.5–5.0 mmol/L), creatinine of 4.91 mg/dL (normal 0.67–1.17 mg/dL) and glucose over 1500 mg/dL (65–200 mg/dL). The complete blood count revealed a haemoglobin of 60 g/L (132–169 g/L), white cell count of 33.99×10³/L (4.22–10.33×10³/L) and platelets of 65×10³/L (160–383×10³/L). His initial liver profile on admission showed an aspartate aminotransferase level of 26 U/L (10–50 U/L), alanine aminotransferase level of 27 U/L (10–50 U/L), alkaline phosphatase of 170 U/L (40–129 U/L) and total bilirubin <0.2 mg/dL (0.2–1.3 mg/dL). His lipase was over 600 U/L (7–59 U/L), triglycerides were 595 mg/dL (50–150 mg/dL), haemoglobin A1c was 12.9% (4.0%–5.6%), thyroid stimulating hormone level was 24.16 µIU/mL (0.4–4.50 µIU/mL) and free T4 was 0.3 ng/dL (0.8–1.8 ng/dL). Coagulation labs were significant for an elevated international normalized ratio (INR) to 3.1 (0.9–1.1), elevated partial thromboplastin time (PTT) to 42.4 s (25.1–36.5 s) and high fibrinogen levels up to 701 mg/dL (190–400 mg/dL).

A CT scan of his chest revealed bilateral pulmonary nodules and consolidations with cavitation and bilateral pulmonary ground glass with mosaic attenuation. A CT scan of his abdomen revealed acute interstitial oedematous pancreatitis. A CT scan of his brain revealed multiple scattered foci of restricted diffusion within the bilateral frontal, right parietal and posterior inferior left temporal lobes consistent with multifocal acute to subacute infarcts. After the CT scan of the brain ruled out an intracranial mass, a lumbar puncture was performed with the following results: glucose—591 mg/dL (40–70 mg/dL), protein—91 mg/dL (15–45 mg/dL) and nucleated cells—1/µL (0–5/µL). Finally, both transthoracic echocardiogram and transoesophageal echocardiogram revealed no evidence of endocarditis. Blood cultures (BD Bactec) grew non-typeable H. influenzae in two out of two sets of aerobic and anaerobic bottles.

Differential diagnosis

The initial differential diagnosis was extraordinarily broad given his presentation of multiorgan failure. The differential for his altered mental status included meningitis, myxoedema coma, drug intoxication, stroke secondary to septic emboli from endocarditis, mycotic aneurysms secondary to sepsis and metabolic encephalopathy secondary to septic shock. The aetiology of his sepsis included any bacterium capable of causing a cavitary pneumonia, endocarditis and meningitis. Streptococcus pneumoniae can cause all three clinical conditions, a cluster of findings termed Austrian syndrome.⁴ Meningitis was effectively ruled out by the cerebrospinal fluid results and endocarditis by the negative echocardiograms. Ultimately, the positive blood cultures for non-typeable H. influenzae revealed the diagnosis. The elevated lipase and beta-hydroxybutyrate indicated coexisting acute pancreatitis and diabetic ketoacidosis. Finally, the differential for the elevated INR, PTT, anaemia and thrombocytopenia included DIC and acute liver failure.

Treatment

The patient received vancomycin, piperacillin–tazobactam, moxifloxacin, meropenem, cefepime and metronidazole within the first 24 hours of admission. This was narrowed to vancomycin, cefepime and metronidazole but after identification and susceptibility of the organism revealed the presence of a beta-lactamase, meropenem was resumed. The patient was continued on meropenem for 3 days and developed cholestasis and hepatitis believed to be secondary to this antibiotic. Five days after cessation of meropenem, his liver enzymes and function tests returned to baseline. Infectious disease consultants became involved in the case and he was eventually narrowed to 2 g of intravenous ceftriaxone. He was found to have mycotic aneurysms on MRI and completed a course of 6 weeks of total therapy. Dermatology performed a punch biopsy, which demonstrated thrombosed vessels with extravasated red blood cells and epidermal necrosis, consistent with purpura fulminans. His hospital course was complicated by myxoedema coma, acute hypoxemic respiratory failure requiring intubation, acute renal failure requiring continuous renal replacement therapy and bilateral pleural effusions requiring chest tubes. His HIV test was negative and immunoglobulin levels and vaccine titers were normal. The only immunocompromising condition identified was his poorly controlled type 1 diabetes.

Outcome and follow-up

The patient was discharged 2 months after admission. He followed up in infectious diseases clinic 1 month after discharge and was in stable condition at the time. The areas affected by the purpura fulminans had eschar formation with minimal purulence. Per the patient’s partner, he had normal cognitive function prior to admission. After discharge, the patient suffered from visual hallucinations and decreased cognitive function, particularly short-term memory. He is being evaluated for Lewy body dementia or another Parkinsonian-like syndrome.

Discussion

Literature review

An extensive literature review was conducted using PubMed and Scopus with the following search terms: “haemophilus influenzae purpura fulminans”, “h. influenzae purpura fulminans”, “non-typeable haemophilus influenzae purpura fulminans” and “non-typeable h. influenzae purpura fulminans”.

A total of two adult cases of H. influenzae causing purpura fulminans were found using the PubMed and Scopus search terms. The first case was reported in 2006, when a 34-year-old woman presented with septic shock and ischaemic injury to her fingers, toes, buttocks, legs and feet. She was treated with ceftriaxone but ultimately needed bilateral below the knee amputations for wet gangrene and her fingers were allowed to auto-amputate. Her laboratory tests demonstrated positive cardiolipin and beta-2-glycoprotein antibodies, suggesting an inherent prothrombotic predisposition.⁵ The second case was reported in 2014, when a 41-year-old man presented with fever, diarrhoea and fatigue. The patient rapidly decompensated, ultimately requiring veno-arterial extracorporeal membrane oxygenation (ECMO) that was later transitioned to veno-venous ECMO. The patient developed purpura fulminans requiring bilateral above the knee amputations and right forearm and left upper arm amputations. The patient died after developing secondary complications with empyema secondary to methicillin-resistant Staphylococcus aureus.⁶

Epidemiology and pathophysiology of H. influenzae

Since the advent and administration of the Hib conjugate vaccine, there has been a dramatic shift of invasive disease attributable to non-typeable bacteria. In 1989, 80% of invasive diseases were caused by Hib, while only 17% of cases were related to non-typeable H. influenzae. By 2008, percentages had shifted, with 3% of invasive cases related to Hib and 68% to non-typeable H. influenzae.^{2 7} Since the widespread implementation of the Hib conjugate vaccine, there has been an increase in the incidence of invasive non-typeable Haemophilus infections. Data from 1999 to 2008 revealed an incidence of 0.99 per 100 000 people per year.² Subsequently, data from 2009 to 2015 revealed an incidence of 1.22 per 100 000 people per year.⁸

Non-typeable H. influenzae makes use of several different virulence factors such as adhesins and pilli to invade the epithelial cells that line the respiratory tract. Although the capsule of Hib acts as a virulence factor preventing phagocytosis, it is also thought to hinder the attachment of the bacteria to the respiratory tree. Capsule-deficient mutants have shown to have a greater affinity and ability to attach to human cells.⁹ Moreover, the bacterium uses different mechanisms to circumvent the innate immune system. The lipooligosaccarides permit evasion of phagocytosis and opsonisation and production of IgA proteases allow the bacteria to populate the respiratory tree through cleavage of IgA immunoglobulins. All these mechanisms could explain how rapidly this infection spreads causing severe multiorgan disease. Invasive disease typically affects children, elderly and those with immunocompromising conditions.¹⁰ Our patient had poorly controlled type 1 diabetes mellitus, which rendered him more susceptible to invasive disease.

Purpura fulminans and H. influenzae

We present the first reported case of non-typeable H. influenzae causing purpura fulminans in an adult patient. There are several different hypotheses regarding the association of infection and sepsis leading to purpura fulminans. The first is through DIC, a condition characterised by dysregulation of the coagulation cascade leading to both a prothrombotic and antithrombotic states. DIC labs were inconclusive in our patient as he had high fibrinogen levels, opposite to what is normally found in DIC. The second mechanism is secondary to deficiencies in protein C, protein S and antithrombin. Proteins C and S serve as natural anticoagulants produced by the liver and are dependent on vitamin K for synthesis.^{11 12} Patients with inherited deficiencies in protein C are more prone to developing warfarin-induced skin necrosis. Given that our patient met the clinical criteria for liver failure, he may have been in a transiently prothrombotic state with depleted protein C and S levels, triggering thrombosis of his skin and the appearance of purpura fulminans. A study by Letrolle et al found that patients with sepsis and purpura fulminans had lower levels of protein S and antithrombin compared with those with sepsis alone and those with sepsis and DIC.¹³ Finally, the manuscript by Gast et al found that their patient, with invasive H. influenzae, had positive antibodies to cardiolipin and beta-2-glycoprotein, which suggests that patients who develop purpura fulminans may have an intrinsic predisposition. Interestingly, protein C and S levels were within normal limits.⁵

Complications

All three patients who developed purpura fulminans secondary to H. influenzae infection suffered complications such as secondary infections, amputations or multiorgan failure. The patients reported by Gast et al and Endo et al both required amputations with the latter patient succumbing from empyema secondary to methicillin-resistant S. aureus.^{5 6} These findings suggest that H. influenzae bacteraemia with concomitant purpura fulminans may be associated with significant morbidity and possible mortality.

Teachable moment

This case report highlights the importance of distinguishing the clinical significance between beta-lactamase producers and extended spectrum beta-lactamase producers. Beta-lactamases inactivate penicillin-based and cephalosporin antibiotics through hydrolysis of the beta-lactam ring. It is crucial to note that the higher generation oxyamino cephalosporins, like ceftriaxone, still maintain their bactericidal activity in the presence of beta-lactamase producers. This contrasts with the extended spectrum beta-lactamases which can hydrolyse the oxyamino cephalosporins.¹⁴ The patient in our case was inappropriately started on meropenem after report of the presence of a beta-lactamase. He suffered severe side effects due to the carbapenems such as acute liver injury and cholestasis, complications that have been well documented in the literature. Using the Naranjo Adverse Drug Reaction Probability Scale, we calculated a score of 5, which indicates that the meropenem was a probable cause of the elevated liver enzymes and cholestasis that we observed.¹⁵ Rarer but fatal complications like the vanishing bile duct syndrome have been reported secondary to meropenem use, highlighting the importance of judicious but appropriate use of the drug.^{16 17}

Learning points.

• Non-typeable Haemophilus influenzae can cause invasive illness in adult patients, particularly those with underlying immunocompromising conditions.

• Sepsis secondary to H. influenzae can cause disruption in the coagulation cascade leading to purpura fulminans.

• There is a clinical and microbiological difference between beta-lactamase and extended-spectrum beta-lactamase producers, with the former being sensitive to oxyamino cephalosporins, like third-generation cephalosporins.