Education and debate

Lesson of the Week: Potentially lethal bacterial infection associated with varicella zoster virus

^a Paediatric Infectious Diseases Unit, Department of Paediatrics, St Mary's Hospital Medical School, London W2 1NY, ^b Department of Paediatrics, St Albans and Hemel Hempstead NHS Trust, Hemel Hempstead HP2 4AD

Correspondence to: Dr Pollard.

Chickenpox is generally considered to be a benign self limiting illness in children. Indeed, mild secondary bacterial infection of the skin, of little clinical importance, is the most common complication of varicella virus infection.^{1 2} There has been a recent increase in reports of serious bacterial infections, however, both during or after chickenpox.

We reviewed the case notes of 13 children (mean age 30 months; seven boys, six girls) who presented to our unit over 12 months (1994-5) with bacterial sepsis associated with chickenpox. We also included one case (case 1) who died of group A streptococcal septicaemia at another hospital.

 Occult bacterial
 infection with group
 A streptococcus or
 Staphylococcus
 aureus may
 complicate
 chickenpox and
 cause potentially
 lethal disease

Case report

An 11 month old girl was admitted with fever, poor feeding, and diarrhoea on the fourth day after the onset of chickenpox. She had a fever of 40°C and a haemorrhagic pustular rash. There was periorbital oedema and conjunctival injection with oral erythema and a 1 cm diameter black necrotic lesion around a vesicle on the dorsum of her left hand. There was no neurological or cardiovascular compromise at presentation.

Twenty four hours later she became shocked with a capillary refill time of four seconds, peripheral core temperature difference of 8°C, blood pressure of 75/40 mm Hg, and a pulse of 150 beats/min. She developed increasing oedema and required supplementary oxygen. Despite resuscitation with colloid and a course of antibiotics she continued to deteriorate and was intubated and mechanically ventilated. Inotropic support and large volumes of colloid were required to correct the shock.

Initial laboratory investigations indicated a haemoglobin concentration of 103 g/l, a white cell count of 7.2 x 10⁹/l, and a platelet count of 119 x10⁹/l with normal clotting. There was hyponatraemia with a plasma sodium of 126 mmol/l. She was treated with intravenous acyclovir, flucloxacillin, and gentamicin. An echocardiogram and a computed tomogram of the brain showed normal functioning.

Incision and drainage of the necrotic hand lesion was performed, with a rapid improvement in her clinical condition; pus from this lesion grew Staphylococcus aureus. Staphylococcal enterotoxins A, C, and D were isolated from this sample.

Results

Features of all 13 cases are summarised in table 1. The mean time to presentation from onset of the chickenpox rash was five days, range two to 14 days. S aureus was isolated from blood cultures in three children and from other sites, including infected skin, nose, and throat, in five children. Group A streptococcus grew in blood cultures from two children and from skin lesions or lymph node in two others. Two children had Gram negative septicaemia, one with Escherichia coli and another with Pseudomonas sp. Six of the children presented with features of toxic shock syndrome. Nine of the 12 children presented with a temperature higher than 39°C. Only three children had a substantially raised white cell count and only five had neutrophil leucocytosis. In four of the children we also measured toxin production from the bacterial isolate. In all four cases either staphylococcal or streptococcal enterotoxins were detected.

Table 1--Clinical and laboratory features of 13 patients with invasive bacterial infection (group A streptococcus or Staphylococcus aureus) following
on from chickenpox
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
                        Days                                                                           Initial
                        since                                                        Temperature       white              Initial            C
                        onset  Organism isolated                                         at             cell           neutrophil        reactive
           Age           of    from blood                                            presentation      count             count           protein   Toxin
Case No  (months)  Sex  rash   (or other site)             Clinical features             (°C)  (x 109/l)   (x 109/l)   (mg/l)   detected
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
 1         24       M     3    Group A streptococcus       Convulsions, shock; died      39.6           11.1               9.1
 2         11       F     4    S aureus (skin)             Shock, haemorrhagic rash      40.0            7.2               3                       SEA, SEC, SED
 3         23       M     2    S aureus                    Toxic shock syndrome,         39.1           28.8              14.9             154
                                                           infected skin lesions
 4         84       F     6    Pseudomonas                 Status epilepticus                            5                 3.2              28
 5          1.5     M     2    S aureus                    Shock                         39.0            6.2               3.8              9
 6          4       M     2    Coliforms                   Irritable, unwell looking     39.0           10                 2.8              <5
 7         36       F     6    S aureus (skin, nose,       Shock, infected skin          39.0           19.6              13.4                     SEA, SEB
                               throat)                     lesions
 8         20       F    14    Group A streptococcus       Lymphadenitis                 39.2           19                12               110
                               (lymph node)
 9         17       M    10    No organism                 Shock                         37.9            5.9               2.3              <5
10         48       M     4    Group a streptococcus       Fasciitis                     39.0           13.2              11.4              83     SPEA
11         17       F     5    S aureus (skin)             Lymphadenitis                 38.5            9.8               7.2
12         60       M     5    S aureus (blood and skin);  Toxic shock syndrome,         36.5            9.4               6.8
                               Group A streptococcus       infected skin lesions
                               (skin, eye)
13         48       F     7    S aureus (skin)             Shock, infected skin          39.5           12.2               8.2              34     SEC
                                                           lesions
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
SEA, SEB, SEC, SED: staphylococcal enterotoxins A,B,C,D; SPEA: streptococcal pyrogenic exotoxin A.

Discussion

Complications of varicella zoster virus infection are diverse and well recognised and include Reye's syndrome, cerebellar ataxia, arthritis, thrombocytopenia, and purpura fulminans¹ associated with low protein C and S concentrations,³ but secondary bacterial infection is the most common complication.^{4 5}

In a population based study conducted over 20 years in Minnesota, 1 in 1000 children with chickenpox required admission to hospital; the most common complications leading to admission were bacterial superinfection in children under 5 years, varicella encephalitis in 5 to 9 year olds, and varicella pneumonia in adults.⁶ Among 2534 patients with varicella seen at one hospital in New York during a five year period, 133 (5.2%) had complications, and of these, 28% had otitis media, 15% bacterial pneumonia, 10% septicaemia, 12% lymphadenitis, 11% cellulitis, 18% abscess, 5% erysipelas, and 3% gangrene.⁵ Most bacterial isolates were group A streptococcus or Staphylococcus aureus. There are no population based studies of complications of varicella in the United Kingdom.

Fever and irritability are typical early features of both varicella virus infection and bacterial sepsis. In uncomplicated varicella infection, constitutional symptoms are usually resolving by three to four days. Secondary bacterial infection may be likely if the child's fever returns or worsens or if the child deteriorates after an initial improvement. In the first three days of varicella infection, however, early bacterial sepsis can be indistinguishable from uncomplicated varicella zoster virus infection. Four of our 13 cases developed bacterial sepsis within three days of onset of the rash. Laboratory investigations were of little help in distinguishing bacterial from viral infection, as white cell count, neutrophil counts, and C reactive protein concentration were not consistently raised in our cases. Therefore, a high index of suspicion is needed to make the diagnosis of bacterial sepsis in any child presenting with varicella virus infection.

S aureus was isolated from blood cultures in three of our patients who presented with features of toxic shock syndrome. The organism was also isolated from infected skin in five children, four of whom presented with shock. Although not yet included in lists of complications of varicella in standard textbooks,^{1 2} staphylococcal toxic shock has been reported in association with chickenpox.^{7 8} Other staphylococcal complications of varicella, including staphylococcal scalded skin syndrome,⁹ pericarditis,¹⁰ and osteomyelitis,¹¹ have also been reported. Staphylococcal pneumonia is well recognised as a complication of chickenpox in adults.¹²

Systemic sepsis with group a streptococcus, complicating chickenpox, is increasingly recognised,^{4 13 14 15 16 17 18 19 20 21} and this organism was isolated from four children in our series. These children may present with streptococcal toxic shock syndrome,^{15 22} necrotising fasciitis,¹⁴ osteomyelitis,²³ pyomyositis,²⁴ gangrene,²⁵ subgaleal abscess,²⁶ arthritis,²⁷ or meningitis²⁸ associated with varicella. Christie et al examined the medical records of 60 children presenting to two centres in the United States with bacteraemia caused by group A streptococcus.²⁹ Seven (12%) children had varicella infection as the underlying diagnosis. In another study of all 37 children with group A streptococcal disease presenting to Memphis children's hospital during an eight year period, 22% (8) of the children had varicella virus as the underlying infection, and 68% of the isolates produced streptococcal pyrogenic exotoxins (SPE A,B,C).¹³

In our series, group a streptococcus infection was associated with fasciitis and local lymph node disease. A series of 14 children presenting over an 18 month period with group A streptococcal necrotising fasciitis, which was associated with varicella infection, has recently been reported. This study showed the difficulty of diagnosing invasive disease on a background of varicella infection.¹⁴ Pain, erythema, and oedema were universal features of group A streptococcal fasciitis, but pain may also herald the onset of staphylococcal scalded skin, complicating varicella.³⁰

In those children presenting with shock, diagnosis is usually readily apparent. Features of toxic shock syndrome include fever, diarrhoea, myalgia, red mucous membranes and lips, strawberry tongue, conjunctival injection, rash, erythema and swelling (and subsequent desquamation) of extremities, tachycardia, hypotension, and neurological dysfunction progressing to coma. Laboratory findings may include a low platelet count, raised transaminase activity, increased plasma urea and creatinine concentrations, electrolyte disturbance, and coagulopathy.³¹ Both group A streptococcal disease and staphylococcal infection may present as toxic shock syndrome.^{11 12 15 22 32 33} Eight of our patients presented with features of toxic shock syndrome and in three of these children enterotoxin producing strains of S aureus were isolated. The staphylococcal enterotoxins and the streptococcal pyrogenic exotoxins belong to a family of toxins which, acting as superantigens,^{34 35 36} stimulate vast numbers of T lymphocytes, causing widespread immune activation, including cytokine production, which may lead to shock.

The reasons for the association of group A streptococcal sepsis with varicella virus infection are not clear. Invasive bacterial infection in varicella zoster virus disease may simply be related to the decreased integrity of the skin as a result of varicella lesions which attenuate the physical barrier to invasion. But this does not explain the late cases of bacterial disease observed up to two weeks after onset of varicella infection,¹⁵ as occurred in one of our cases. An alternative explanation is that varicella infection impairs host immunity. A transient granulocyte killing defect has been reported in one case.³⁷ The possibility that some viruses might encode proteins (virokines) which interfere with immune responses by blocking cytokines or complement^{38 39} is intriguing but has yet to be shown in varicella virus infection.

These cases highlight the seriousness of bacterial superinfection as a complication of chickenpox in children. The possibility of bacterial sepsis, especially caused by group A streptococcus or staphylococcus, should be considered in any child with varicella virus infection who has persistent or recurrent fever after the third day of the illness, or when signs of systemic toxicity appear. Early antibiotic administration and surgical drainage of infective foci may save the lives of patients with septicaemia or toxic shock syndrome. Bacterial sepsis, along with the occurrence of other potentially lethal complications of varicella, adds weight to the arguments for inclusion of varicella virus vaccine into childhood immunisation schedules in the United Kingdom, as is now being considered in the United States.⁴⁰

Funding: None

Conflict of Interest: None

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