Infectious purpura fulminans associated with pneumococcal septicaemia in a patient with unacknowledged functional asplenia

Abstract

Purpura fulminans (PF) is a life-threatening complication of septic shock that can occur due to disseminated infections with Streptococcus pneumoniae. The spleen is an important organ in the immunisation process against encapsulated bacteria. Patients with asplenia, either functional or anatomical, are therefore at increased risk of developing serious infections and complications, such as PF, if infected with such bacteria.

This case report presents a woman in her late 40s with unacknowledged functional asplenia who was admitted to the hospital with signs of an acute disseminated infection causing septic shock, signs of disseminated intravascular coagulation and infectious PF. A few days after admission, the blood cultures showed growth of S. pneumoniae. With early sepsis treatment, the patient survived although with some complications. Clinical presentation, investigations, differential diagnosis, treatment and outcome are presented. Treatment and early recognition of PF are presented and discussed. Relevant recognition and preventative treatment strategies for patients with asplenia are also reviewed and discussed.

This case demonstrates the importance of early recognition and treatment of PF in septic patients and the importance of preventive treatment strategies for patients with asplenia to avoid serious infections and complications.

Background

Purpura fulminans (PF) is a disease with acute onset with extensive cutaneous bleeds presenting as erythematous mottled lesions that rapidly progresses to haemorrhagic necrotic lesions in affected structures.¹ PF usually affects individuals with the impaired immune system, although it can in rare cases complicate bacterial septicaemia in immunocompetent patients.² PF can be associated with severe sepsis and can worsen the prognosis drastically with the development of disseminated intravascular coagulation (DIC), cutaneous bleeds and circulatory collapse.³ The prognosis is poor with a mortality rate up to 40%. Complications after PF usually involve amputation or skin grafts of involved structures if normal healing does not occur.⁴

The spleen is an important structure in immunisation against encapsulated bacteria such as Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae type b (H. influenzae) and Neisseria meningitidis (N. meningitidis) among others. Asplenia can occur either as anatomical absence of the spleen or as functional asplenia where the function is impaired.⁵ Patients without a spleen have a greater risk of severe sepsis by encapsulated bacteria and these infections often result in death with mortality rates between 50% and 70%. The majority of infections in patients with asplenia are caused by S. pneumoniae. ⁶

The case presented is a patient with unacknowledged asplenia who presented with severe sepsis caused by S. pneumoniae and developed infectious PF with DIC as a complication. Clinical presentation, investigations, differential diagnosis and treatment are presented. Treatment and prophylactic interventions of patients with asplenia are discussed. PF as a complicating factor to severe sepsis is also discussed, and current treatment options are presented.

Case presentation

A woman in her late 40s was admitted to the emergency department with a 2-day history of dry cough, muscle soreness, fever and increasing shortness of breath. Previously known with diabetes mellitus type 2 (DMT2) and a pulmonary embolism from a deep vein thrombosis years prior to this incidence.

On initial examination, she was found to be afebrile but hypotensive with a blood pressure of 60/35 mm Hg and tachycardia with a heart rate of 130 beats per minute. She was tachypnoeic with a respiratory rate of 44 per minute and had signs of decreased periphery perfusion with extended capillary filling time and cold extremities with signs of cyanosis. She had developed diffusely mottled lesions on face, trunk and extremities (figure 1).

Figure 1.

Mottled skin lesions at the time of hospitalisation are shown on the leg (A) and hand (B).

Initial examination of the abdomen and cognitive function was normal, and auscultation of the respiratory system was with normal lung sounds.

She was acutely given intravenous fluids, oxygen and norepinephrine because of haemodynamic instability and hypoxia. Blood cultures were obtained, and she was started on broad-spectrum antibiotics according to regional guidelines on the suspicion of septicaemia.

Over the next few days, her condition worsened, and she developed signs of DIC and multiorgan failure. She displayed signs of acute tubulointerstitial nephritis and was started on haemodialysis. She was intubated and put on respiratory support due to respiratory failure; there were signs of hepatocellular dysfunction, and she became increasingly unresponsive.

Ecchymosis began to appear on both legs, hands, fingers and in the face. The skin lesions gradually progressed with bullae and sloughing of the skin in the face and on the extremities. The fingers and the lower extremities became cold and black indicating necrotic changes (figure 2). This was consistent with the development of infectious PF with DIC, a complication of sepsis.

Figure 2.

Necrotic skin lesions shown on hands (A) and the lower extremities (B) compatible with infectious purpura fulminans.

Investigations

The initial blood analysis showed signs of septic shock with metabolic acidosis (pH 7.18) that was partly respiratory compensated, high C reactive protein (CRP) (197 mg/L), increased white blood cell count (25.4×10⁹ /L) and increased lactate dehydrogenase (726 U/L). Coagulation parameters showed prolonged coagulation time (activated partiel thromboplastin time, APTT over 120 s), low platelet count (91×10⁹/L), low levels of coagulation factors II, VII, X (0.33) and a decreasing fibrinogen (1.2 µmol/L) that all indicated development of DIC.

The kidney showed signs of failure with high creatinine levels (325 µmol/L) and a low filtration rate (estimated glomerular filtration rate, eGFR 14 mL/min). The liver parameters showed increased alkaline phosphatase (266 U/L) and alanine aminotransferase (97 U/L) due to hepatic hypoperfusion. The patient showed no signs of cerebral involvement at the time of admission with normal cognition with a Glasgow Coma Scale of 15, normal responsive pupils and no neck stiffness. She later became unresponsive and a CT scan of the brain was therefore performed. The CT scan showed no abnormalities. Because the patient had developed DIC, it was not possible to perform a lumbar puncture without a risk of bleeding.

A CT scan of the thorax and abdomen showed no pulmonary embolism, pneumothorax or lung infiltrations. It was however discovered on the scan that the patient’s spleen was very small (figure 3). A CT scan from 2014 showed similar findings of a rudimentary spleen. This was unfortunately not described at the time and hence not acted on. A blood smear was performed on peripheral blood to investigate the splenic function. This showed the presence of Howell-Jolly bodies, which could indicate a decreased function of the spleen.

Figure 3.

CT scan of the spleen. The spleen was a 5.1×0.8x0.8 small brim.

An examination of the patients’ ears, nose and throat was made to find the initiation site of the infection but did not find anything abnormal. A transthoracic echocardiogram and transesophageal echocardiogram were also performed but showed no sign of endocardial infection that could be the cause of the infection. Blood cultures taken at the time of admission showed growth of S. pneumoniae, susceptible to benzylpenicillin.

Differential diagnosis

The clinical presentation of the patient could be caused by several different diagnoses. Due to the former history of pulmonary embolism, this was suspected. An acute CT scan of the thorax at the time of admission did however exclude a pulmonary embolism, pneumothorax or lung infiltrations.

The patient’s clinical presentation with hypotension, tachypnoea and multiorgan failure indicated severe septic shock. This can be caused by different pathogens.

Staphylococcus aureus (S. aureus) is a naturally occurring skin bacteria that can cause infections in soft tissue, bone, endocardium and blood if it enters the bloodstream. If infections spread to the bloodstream, it can cause severe sepsis and DIC. S. aureus has a variety of mechanisms by which it can evade the immune system, colonise the bloodstream and cause sepsis. Septicaemia with S. aureus can be associated with DIC and the bacteria can produce a high number of toxins that can worsen the severity of the infection.⁷

Toxic shock syndrome (TSS) is a toxin-mediated disease caused by a toxin produced by S. aureus and usually induced by tampon use. TSS can be potentially fatal. A gynaecological examination was performed on the patient and was found normal without signs of infection. No skin lesions that could be the entry point of the infection were found.

The purpuric ecchymosis’ progression to necrotic lesions and the laboratory findings indicated infectious PF with DIC. Infectious PF is rarely associated with S. aureus infections, although it has been described.⁸ There was no growth of S. aureus in the blood cultures. The above findings make it unlikely that the cause of septic shock and PF in this case was mediated by an S. aureus infection.

PF is often associated with N. meningitidis especially in neonates and young children. This pathogen was however not suspected in this case because the clinical presentation and examination showed no stiffness of the neck, petechial rash or cerebral affection.

Because of the presenting symptoms of tachycardia, tachypnoea, difficulty breathing, cold clammy skin and as it was discovered that the patient suffered from functional asplenia, the most likely diagnosis was severe sepsis caused by S. pneumoniae. An infection with S. pneumoniae could explain the severity of the pneumococcal infection as the spleen is vital in the immune system against infections with encapsulated bacteria.⁵ Most cases of bacteraemia caused by S. pneumoniae the initiation of the infection is the lungs where a pneumonia progresses to bacteraemia.⁹ It was however never discovered from where the pneumococcal septicaemia initiated, but in patients with asplenia the primary focus of the infections are rarely identified.^{10 11} Cases with RF associated with S. pneumoniae are not common but have been described.¹² Positive findings of S. pneumoniae in the blood cultures confirmed this diagnosis.

Furthermore, the patient suffered from DMT2 which is associated with an increased risk of getting serious infections including sepsis.¹³ Diabetes could be a contributing factor to the severity and vast progression of the infection.

Treatment

The patient received piperacillin–tazobactam, meropenem, gentamicin and clindamycin within the first 24 hours of admission on the suspicion of TSS and severe sepsis. This was narrowed to clindamycin and meropenem until the blood cultures came back positive for S. pneumoniae. The antibiotics were then switched to benzylpenicillin as the bacteria were susceptible to this. Clindamycin was maintained for a few additional days in combination with benzylpenicillin. Clindamycin has a broader range than benzylpenicillin and is among others effective against both group A and B streptococci, pneumococci and S. aureus.¹⁴ Clindamycin was maintained because of its anti-inflammatory properties by lowering the toxin production in infections with group A and B streptococci, and therefore possibly lower the severity of the infection. Although there is not enough data to support this, this combination is still recommended.¹⁴

After 16 days of treatment with benzylpenicillin, there were temperature risings and increasing CRP, and the patient was therefore switched to ceftriaxone to broaden the antibiotic spectrum. A few days after initiating this treatment there was a rise in eosinophilic leucocytes, which indicated drug fever rather than a new infection, and ceftriaxone was therefore discontinued. After a few days without antibiotic treatment, the patient’s inflammatory parameters started to rise again. A return of the initial infection was not suspected but an infection in the necrotic skin lesions seemed to be the reason. Piperacillin–tazobactam was started on this indication and CRP started to decrease again. An overview of administered antibiotics, CRP and leucocytes is shown in figure 4.

Figure 4.

Infectious graph and antibiotic treatments. Each box indicates 1-week duration, with a total of 10 weeks. The green graph shows leucocytes and the black shows C reactive protein levels. Treatment mostly consisted of benzylpenicillin for the initial treatment of pneumococcal septicaemia. Secondary infections were treated with piperacillin–tazobactam combination and meropenem.

Her hospital stay was complicated by acute kidney failure, which required haemodialysis, and respiratory failure which required intubation and respiratory support. The septicaemia by S. pneumoniae was complicated by RF with DIC. This was treated by giving low-molecular-weight heparin to prevent blood clotting.

The skin lesions that began as mottled lesions quickly evolved into ecchymosed skin lesions with bullae and eventually necrotic areas that were a sign of the development of PF as a complication to the pneumococcal sepsis. The necrotic lesions on the lower extremities required skin transplantation and the necrotic finger amputation.

Outcome and follow-up

The patient survived the severe infection with S. pneumoniae, but had complications because of the development of necrotic skin lesions due to infectious PF. The patient was hospitalised at the Department of Infectious Diseases (ID) for 5 weeks initially at the ICU and subsequently at the ID ward. Afterwards, she was transferred to the Department of Orthopaedic Surgery where she underwent surgical revision with the removal of necrotic tissue on the lower extremities and had skin transplantations by plastic surgeons, where the skin was grafted from her abdomen and transplanted to the lower extremities after necrotic tissue was removed. This had to be done multiple times over the following weeks. After initial treatment of the pneumococcal infection, the patient unfortunately had episodes with recurring CRP risings with signs of infection that needed treatment with broad-spectrum antibiotics and extended her hospital admission period.

The necrotic skin on the truncus was superficial and healed gradually throughout the admission period with no sign of secondary infection. Necrosis on fingers on both hands unfortunately needed amputation. On the right hand, it was only the first finger and on the left hand, all five fingers were amputated at the interphalangeal joint. There were no signs of compartment syndrome in the tissues that were affected by necrosis, but the right foot showed signs of a pointed foot as a consequence of the septic shock and multiorgan failure. There was decreased motion of both ankles that needed physiotherapy to prevent impaired function.

As it was discovered on a CT scan that the patient had a hypofunctional spleen, the patient should be started on prophylactic phenoxymethylpenicillin when the pneumococcal infection was cleared. Furthermore, the patient should be vaccinated against encapsulated bacteria to prevent future infections. Preventative treatment strategies for patients with asplenia are elaborated further in the discussion.

Because the patient’s condition with asplenia had been overlooked on a CT scan prior to the admission, the patient was informed that she could apply for compensation as the earlier findings should have resulted in interventions with relevant vaccinations and prophylaxis.

Discussion

PF: presentation and treatment

PF is a rapidly progressive syndrome that consists of intravascular thrombosis and necrosis of the skin. There are three types of PF: neonatal PF, idiopathic PF and infectious PF.^{15 16}

Neonatal PF is caused by a congenital deficiency of protein S or C. Congenital protein C deficiency is more common than protein S deficiency and can either be caused by heterozygous or homozygous gene mutation. The complications vary from mild to severe, where a homozygous gene mutation gives the worst outcome. In severe cases, the child can develop PF within a few hours of birth, resulting in skin necrosis and gangrene of the limbs and digits. Blindness and cerebral damage are also common sequelae.¹

Idiopathic purpura is a very rare complication, and the pathogenesis and causes of this are not fully known. It can be caused by acquired deficiency of protein S, rarely protein C, in conjunction with a postinfectious complication. The protein S deficiency is attributed to the development of cross-reacting IgG autoantibodies binding to protein S and increasing the clearance from the bloodstream. Because of the protein S deficiency, protein C becomes hypoactivated and blood clotting in the vessels is increased. The most associated pathogens with this are Varicella and Streptococcus infections. Postinfectious PF should be considered if DIC and PF occur in an otherwise healthy child.^{1 17}

Infectious PF is a rare complication but is often associated with acute onset of sepsis symptoms with profound hypotension, large purpuric skin lesions, fever and DIC. Infectious PF is often associated with sepsis caused by endotoxin-producing bacteria such as N. meningitidis. Endotoxin-producing bacteria can stimulate an inflammatory response that cause disturbance in the coagulation system, resulting in DIC and septic shock.^{15 18} Hypoperfusion of periphery tissue associated with sepsis and infectious RF is an important factor in the development of tissue necrosis. In septic shock, hypoperfusion is usually most pronounced in distal extremities and tissue necrosis is therefore usually most prevalent here.¹⁹ Additionally, necrosis is caused by microthrombi in the small vessels that impair the blood flow. The pathogenesis of RF is complex but ultimately results in a consumption coagulability where procoagulant and antifibrinolytic changes are induced by stimulating coagulation factors and inhibiting protein C and S to stimulate coagulation.¹⁹

Meningococcal septicaemia complicated by PF is the most common form but is mostly seen in neonates and children. It occurs between 10% and 20% of the cases.¹ S. pneumoniae is a less common cause, but cases have been described and should especially be suspected in patients with immunosuppression or patients with functional or anatomical asplenia.1 3 12 20–22 Other pathogens that can cause infectious PF are group A and B streptococci, H. influenzae and S. aureus. ¹

In relation to this case, it is worth mentioning that the patient’s comorbidities of DMT2 may have contributed to her risk of getting infections. The patient was diagnosed with DMT2 several years prior to this incident, and approximately a year before this she started treatment with insulin because of dysregulated DMT2. As mentioned earlier, DMT2 increases the risk of getting infections, for example, several studies have reported increased risks of getting lower respiratory tract infections.²³ Hyperglycaemia in patients with diabetes both makes optimal conditions for bacterial growth and impairs the immune system in various ways, which makes patients with diabetes more susceptible to infections.²⁴ This could influence the severity of the infection in this case.

Pneumococcal infections that become bacteraemia and subsequently septicaemia are rare. Even though patients without a functional spleen are more at risk of getting serious infections with encapsulated bacteria, it is still rare that pneumococci cause septicaemia and ultimately infectious RF. It is therefore not unlikely that the patient has had a non-functional spleen for many years without developing other serious infections.

In the treatment of infectious RF, the focus should mainly be on treating the underlying cause. Infectious RF is mostly associated with sepsis and is managed by given broad-spectrum antibiotics, haemodynamic support with intravenous fluids and inotropic medications. Correction of electrolyte imbalances and acid–base disturbances is also important.²⁵

It is shown through multiple studies that there is a good effect when using protein C replacement therapy through the administration of fresh frozen plasma as it reduces necrosis and can prevent the need for amputations. This is because acquired protein C deficiency is a central part of the pathology in meningococcaemia associated with infectious RF that leads to thrombosis and tissue necrosis.^26–29 Studies on the effect of protein C replacement therapy in treating RF caused by pneumococcal sepsis are however sparse.

Heparin, either unfractionated or low molecular weight, can be used as an immediate intervention against the hypercoagulability seen in these patients as it has an immediate anticoagulant effect.²⁵ The overall effect of heparin use in these patients is however not sufficiently investigated.¹⁹ Randomised controlled trials are needed to assess the effect of protein C replacement therapy and other treatment interventions in the treatment of infectious PF before general guidelines can be made. The most important part of treating infectious RF remains to treat the underlying cause of infection. This is done by determining the causative bacteria and choosing an effective antibiotic regime.

Asplenia: treatment and preventative strategies

Asplenia can be functional or anatomical. Functional asplenia can either be congenital or acquired secondary to many other conditions such as severe infections, sickle cell disease, coeliac disease, hepatic cirrhosis, sarcoidosis, systemic lupus erythematosus and other autoimmune diseases.^{5 30 31} It is unknown why the patient had asplenia as she had no history of any of the mentioned diseases.

The primary function of the spleen is filtration and destruction of senescent red blood cells and in immunisation against encapsulated pathogens.⁵ Patients with functional asplenia are therefore more exposed to infections with bloodborne parasites such as malaria and infections with encapsulated bacteria such as S. pneumoniae, H. influenzae and N. meningitidis. Although the highest risk of infections is in newborns and young children, adults also have an increased risk of infections (11 to 14 per 100 person-years), especially of fulminant sepsis referred to as overwhelming post-splenectomy infection.^{6 10 32} Severe infections in patients with asplenia are associated with high mortality rates between 50% and 70% if no preventative strategies such as vaccinations or prophylactic antibiotics are applied.³²

To investigate if the splenic function is impaired, peripheral blood smears can be investigated for Howell-Jolly bodies that are remnants from erythrocytes that are usually removed by the spleen. The presence of Howell-Jolly bodies can indicate asplenia or functional hyposplenism.⁶

Preventative measurements against severe infections in post-splenectomy patients or patients with asplenia/hyposplenia have been described in Australian guidelines.³³ Preventative strategies include vaccinations, prophylactic antibiotics and education of the patient and family.

Vaccination is an effective and safe way to induce immunisation in patients with impaired splenic function. It is recommended that patients receive vaccination against pneumococci, meningococci, H. influenzae type b and influenza. Vaccination against COVID-19 should also be prioritised as a study have shown that asplenic patients have an increased mortality risk when infected with the coronavirus.³⁴ Both a 13-valent pneumococcal conjugate vaccine and a 23-valent polysaccharide pneumococcal vaccine should be given to ensure immunisation. Vaccinating against meningococcal disease should include the conjugate vaccine for serogroups A, C, Y and W-135 (MenACWY) and the vaccine for serogroup B (MenB). Annual influenza vaccination and vaccination against H. influenzae type b infection are recommended. In Denmark, vaccination with H. influenzae type b has been implemented in the national childhood vaccination programme since 1993 and a 13-valent pneumococcal vaccine since 2007. Patients born before the implementation of these programmes should however receive these vaccines as well.

Post-splenectomy patients and patients with functional asplenia should take daily prophylactic antibiotics. It is recommended for adults to take amoxicillin 250 mg daily or phenoxymethylpenicillin 250 mg two times per day. There is currently no consensus in guidelines on the duration of daily prophylactic antibiotics that should be taken. Australian guidelines suggest 3 to 5 years for post-splenectomy patients. Lifelong antibiotic prophylactics should be considered as there is a lifelong increased risk of sepsis in these patients. UK guidelines recommend lifelong prophylactic antibiotics to hyposplenic patients up to 16 years and over 50 years, patients who have had previous invasive pneumococcal disease and patients with inadequate response to pneumococcal vaccinations.³⁵ Emergency antibiotics should be given to patients with instructions to take in case of unexplained fever, chills, malaise and other symptoms of infection and to contact emergency care units for immediate treatment.

Lastly, it is important to educate the patient and family about the risks associated with asplenia or hyposlenism and the precautions that need to be taken.³²

No sufficient guidelines currently exist in Denmark. There is a need for the implementation of general guidelines for the treatment and prevention of serious infections in patients with asplenia or hyposplenism.

A case of severe pneumococcal sepsis complicated by infectious PF in a patient with unacknowledged asplenia was presented. The condition required intensive supportive care with a long admission period that was complicated by multiorgan failure, multiple necrotic skin lesions and necrosis of fingers on both hands. Treatment included different antibiotic regimes but was narrowed to benzylpenicillin when S. pneumoniae was identified as the causative pathogen. The necrotic skin lesions ultimately needed skin grafts or amputations. This case demonstrates the importance of preventative and treatment strategies in patients with asplenia as infections in this patient population can develop quickly and progress to severe sepsis with complicating factors such as infectious PF with DIC.

Learning points.

• Infectious purpura fulminans is a serious and life-threatening condition that may be survived if early relevant sepsis treatment is applied.

• Functional asplenia is important to detect on routine imaging, as the consequences of capsular bacterial infections may be severe and potentially deadly.

• If impaired splenic function is discovered in a patient, it is crucial that relevant vaccinations, prophylactic antibiotics and patient education are initiated to avoid serious infections.

Ethics statements

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