Toxic shock syndrome: the great masquerader

Abstract

Toxic shock syndrome is a rare but potentially lethal toxin-mediated illness that can be caused by streptococcal and staphylococcal species. It initially presents as a febrile illness that rapidly progresses to multiorgan dysfunction, hence a high index of suspicion coupled with rapid verification of the diagnosis and aggressive treatment is required to improve the outcome of the disease. A 23-year-old man presented with high-grade fever associated with headache, retro-orbital pain, gastroenteritis and gum bleeds. Treatment was initiated keeping in mind the possibility of dengue haemorrhagic fever. However, further clinical deterioration led us to re-examine our patient, revealing an old neglected wound. Microbiological confirmation of methicillin-resistant Staphylococcus aureus from the wound swab and prompt institution of appropriate treatment led to a favourable outcome in a case known to be associated with serious morbidity and mortality.

Background

Toxic shock syndrome (TSS) is an uncommon disease with multisystem involvement and a poor outcome unless diagnosed early. It was described by Todd et al ¹ and was not well known until an epidemic in 1981 established causality between TSS and tampon use. Several cases of TSS have been reported in non-menstruating women and also in men suggesting that multiple mechanisms of causation exist.^{2 3}

A separate entity known as recurrent menstrual TSS has also been described and is found in almost one-third patients who have previously had TSS. It is attributed to two factors, namely persistent colonisation with toxigenic strains of Staphylococcus aureus and persistent absence of neutralising antibody.⁴ However, this phenomenon is less commonly seen in cases of non-menstrual TSS.

Diagnosis of TSS is based on clinic-laboratory criteria as well as culture and identification of the causative organism, but in most cases the condition must be pre-emptively treated based on the degree of clinical illness in the patient. Thus, the diagnosis is often retrospective in nature and treatment must be started empirically.

The clinical picture is similar to several other commonly encountered diseases such as viral exanthems, dengue haemorrhagic fever, scrub typhus^{4 5} which are more commonly encountered in India. The incidence of TSS in India is unknown and its occurrence is reported in a few isolated case reports.^{6 7} The delay in identification usually leads to poorer outcomes in such cases, hence awareness of the presentation and clinical course is necessary for early diagnosis and institution of appropriate therapy.

Case presentation

A 23-year-old man, resident of Delhi, with no known comorbidities, presented with high-grade fever (38.9°C) with chills and rigor with no diurnal variation or precipitating factors, relieved by antipyretics for 5 days prior to admission. This was associated with severe headache and retro-orbital pain without nausea, vomiting or redness of eyes. He also reported 4–5 episodes of loose stools in the past week and mild bleeding of gums on brushing his teeth.

On presentation, the patient was febrile. Glasgow coma scale (GCS): E2M2V4 Pulse: 121 beats/min, blood pressure: 70/40 mm Hg, Respiratory rate (RR): 20/min and was maintaining an oxygen saturation of 96% on room air.

On examination, the patient had conjunctival suffusion and a generalised erythematous rash with cold extremities. There were no signs of pallor, icterus or bleeding into skin or other mucosae. The patient had been in Delhi for the past 1 year and had no history of travelling to forested or hilly areas. There was no organomegaly, neck rigidity or any focal neurodeficits. The systemic examination was within normal limits.

Investigations

Laboratory evaluation revealed thrombocytopaenia (40 000/mm³) and leucocytosis (16x10⁹/L) with deranged renal parameters (urea=42 mg/dL, creatinine 1.5 mg/dL), hyperbilirubinaemia (total bilirubin=1.6 mg/dL direct fraction=1.2 mg/dL) and mild transaminitis (aspartate transaminase 94 IU/L) (table 1).

Table 1.

Routine investigations

Date	03 January 2018 (at admission)	04 January 2018	07 January 2018	09 January 2018
Haemogram
HGB (g/dL)	13.3	12.2	11.6	11.6
HCT (%)	39.2	35.9	34.4	35.0
PLT (/μL)	40 000	70 000	62 000	1 50 000
TLC (/mm3)	16 000	14 000	11 400	7300
Renal function tests
Urea (mg/dL)	42	49	78	38
Creatinine (mg/dL)	1.5	1.5	0.9	0.3
Calcium (mg/dL)	7.5	7.1	7.2	7.5
Phosphate (mg/dL)	3.5	2.9	3.3	3.3
Uric acid (mg/dL)	4.5	8.0	8.2	4.3
Na+ (mEq/L)	138	147	143	143
K+ (mEq/L)	3.6	3.5	3.9	4.2
Liver function tests
Bilirubin (total) (mg/dL)	1.6	0.9	0.7	0.8
Direct (mg/dL)	1.2	0.8	0.6	0.6
Indirect (mg/dL)	0.4	0.1	0.1	0.2
Protein (total) (g/dL)	5.0	5.0	5.3	5.3
Albumin (g/dL)	2.5	2.5	2.8	3.0
Globulin (g/dL)	2.5	2.5	2.5	2.3
SGOT (IU/L)	94	136	139	75
SGPT (IU/L)	33	28	47	40
ALP (IU/L)	251	296	200	175
PT (seconds)	17.1
INR	1.5
Urine examination
Protein	2+	–	1+	–
Red blood cells	40–50	–	1–3	–
White blood cells	2–5	–	Nil	–

HGB, Hemoglobin; HCT, Hematocrit; INR, Internationalized Normalized Ratio; PLT, platelet count; PT, Prothrombin Time; SGOT, serum glutamic oxaloacetate transaminase; SGPT, serum glutamate pyruvate transaminase; TLC, total leucocyte count.

As the patient presented with shock, bedside ultrasound was done, which revealed distended inferior vena cava (without collapsibility) and bilateral B-profile in lungs, suggestive of cardiogenic shock. ECG revealed broad QRS complexes and ST segment depression, likely due to subendocardial ischaemia. A room air arterial blood gas showed pH=7.30 with bicarbonate of 22 mEq/L, partial pressure of carbon dioxide of 28 mm Hg and lactate 4.6 mmol/L, suggestive of uncompensated metabolic acidosis. Cardiac enzymes were ordered looking at ECG changes which revealed positive qualitative troponin I and elevated N-terminal probrain natriuretic peptide (10 600 IU).

Bedside echocardiography was done, which showed regional wall motion abnormality and poor LV contractility with ejection fraction—35%–40% without signs of pericardial effusion. Thus, a cardiac tamponade was ruled out as a cause of cardiogenic shock. The regional wall motion abnormality along with decreased ejection fraction and tachycardia were suggestive of a diagnosis of myocarditis. This was further confirmed by the elevated N-terminal probrain natriuretic peptide levels along with positive quantitative troponin I.

The fever workup was negative (dengue NS1 and IgM, scrub typhus, leptospira, malaria and blood culture) (table 2). Creatine kinase was significantly elevated (360 IU). Urinalysis was within normal limits. Minibronchoalveolar lavage revealed insignificant colonies of Acinetobacter species.

Table 2.

Etiological evaluation

Lactate dehydrogenase (U/L)	416 U/L (160–450 U/L)
Creatine kinase	360 μg/L (10–120 μg/L)
Thyroid profile	Within normal limits
Blood culture	Sterile
Chest X-ray	Normal study
Widal test	<1:40
ELISA and IFT scrub typhus	Negative
Malaria (card and smear)	Negative
IgM dengue and NS1	Negative
ELISA leptospira	Negative
Synovial aspirate
Physical character	Clear
Total cell count	100 cells
Differential count	Polymorph—55% Lymphocytes—45%
Gram stain	Negative
Culture	Sterile
Pus swab from left knee	Methicillin-resistant Staphylococcus aureus sensitive to clindamycin, linezolid and rifampicin
Minibronchoalveolar lavage	<103 colonies of Acinetobacter baumannii

IFT, immunoflourescence testing.

Differential diagnosis

Thus, on initial presentation, it appeared to be a case of fever with hepatorenal dysfunction and myocarditis presenting with shock. The differentials kept were:

1. Dengue haemorrhagic fever.

2. Scrub typhus.

3. Leptospirosis.

4. Severe malaria.

5. Viral myocarditis with cardiogenic shock (eg, Coxsackievirus).

6. Sepsis with septic shock.

7. TSS.

Treatment

He was given a fluid bolus with Ringer’s lactate (500 mL over 10 min) which did not improve his vitals. In view of shock refractory to fluids and poor sensorium, the patient was intubated electively and started on inotropes (norepinephrine at 25 μg/min) through a central venous cannula.

Following intubation and mechanical ventilation, the ECG changes improved and the patient was shifted to the intensive care unit and kept under close monitoring. However, the patient did not respond to supportive therapy and developed increasing ventilator requirements and worsening biochemical parameters on the second day of his illness. With no specific diagnosis, we re-examined the patient and found a small 2×3 cm crusted wound below his left knee (figure 1). This had been missed on the initial evaluation as neither the patient nor his family had concerned about the lesion, ascribing it to folliculitis. This shifted our attention to the possibility of a complicated skin infection.

Figure 1.

The lesion below the left knee on presentation.

An ultrasound of the left knee was done which did not show any underlying soft-tissue collection. Joint fluid aspirate had 100 cells (polymorphs—55% and lymphocytes—45%). A pus swab was sent from the wound over the left knee after removing the overlying crust which revealed significant colonies of (methicillin-resistant S. aureus, MRSA) sensitive to linezolid and clindamycin (for complete antibiotic susceptibility profile please refer to table 3). Toxin testing could not be done due to unavailability of the test at our centre. The diagnosis of TSS was considered as the patient fulfilled the diagnostic criteria (table 4). He was subsequently started on intravenous clindamycin and linezolid.

Table 3.

Antimicrobial susceptibility profile of pus swab taken from lesion near left knee organism cultured: methicillin-resistant Staphylococcus aureus

Antibiotics	Sensitivity pattern
Amikacin	Sensitive
Amoxycillin–clavulanic acid	Resistant
Cefoxitin	Resistant
Cotrimoxazole	Sensitive
Ciprofloxacin	Resistant
Erythromycin	Resistant
Linezolid	Sensitive
Netilmicin	Sensitive
Penicillin	Resistant
Teicoplanin	Sensitive
Vancomycin	Sensitive
Rifampicin	Sensitive
Clindamycin	Sensitive

Table 4.

Centers for Disease Control and Prevention case definition 2011 for toxic shock syndrome and it conformity with our case, an illness with the following clinical manifestations¹²

Symptoms/signs/ examinations	Explanation	Present case
Fever	Temperature greater than or equal to 102.0°F (greater than or equal to 38.9°C).	Yes
Rash	Diffuse macular erythroderma.	Yes
Desquamation	1–2 weeks after onset of rash.	Yes
Hypotension	Systolic blood pressure less than or equal to 90 mm Hg for adults or less than fifth percentile by age for children aged less than 16 years.	Yes
Multisystem involvement (three or more of the following organ systems):
Gastrointestinal	Vomiting or diarrhoea at onset of illness.	Yes
Muscular	Severe myalgia or creatine kinase level at least twice the upper limit of normal.	Yes
Mucous membrane	Vaginal, oropharyngeal or conjunctival hyperaemia.	Yes
Renal	Blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or urinary sediment with pyuria (greater than or equal to five leucocytes per high-power field) in the absence of urinary tract infection.	No
Hepatic	Total bilirubin, alanine aminotransferase enzyme or aspartate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory.	Yes
Haematologic	Platelets less than 100 x 109/L	Yes
Central nervous system	Disorientation or alterations in consciousness without focal neurological signs when fever and hypotension are absent.	Yes
Laboratory criteria for diagnosis: negative results on the following tests, if obtained
Blood or cerebrospinal fluid cultures (blood culture may be positive for Staphylococcus aureus)		Negative cultures
Negative serologies for Rocky Mountain spotted fever, leptospirosis or measles		Yes

Outcome and follow-up

After 3 days of therapy (day 6 of hospitalisation), the patient began to show signs of improvement. Inotropic support was gradually tapered and he was extubated after a successful spontaneous breath trial. On day 4 of antibiotic therapy, exfoliative changes were noticed over his forearm that gradually spread all over his body, retrospectively confirming the diagnosis of TSS. A skin biopsy was sent which revealed small vessel vasculitis and ischaemic epidermal changes suggestive of infection-induced immune complex deposition (figures 2–4).

Figure 2.

A low power view of skin punch biopsy shows epidermal necrosis (black arrow) and leucocytoclastic vasculitis (blue arrows) involving the dermal blood vessels. (Stain: H&E, magnification: x100).

Figure 3.

Ischaemic and spongiotic epidermis (black arrow) (Stain: H&E, magnification: x200).

Figure 4.

Arterial wall undergoing necrosis with neutrophilic perivascular inflammation, nuclear fragmentation (black arrow) and extravasated red blood cells (blue arrow). (Stain: H&E, magnification: x400).

Follow-up echocardiography was done which revealed resolution of the regional wall motion abnormality noted on admission with normal ejection fraction.

The patient was treated with 7 days of intravenous antibiotics with gradual improvements in clinicolaboratory parameters. He was discharged after completing 8 days of antibiotic therapy and is doing well on follow-up after 2 months, with no recurrence of symptoms.

Discussion

TSS is characterised by acute, toxin mediated, progressive multiorgan failure.

The exotoxins of S. aureus and group A Streptococcus act like superantigens and cause the immune response leading to its florid clinical features. These organisms can secrete toxins from a small or hidden focus of infection making the diagnosis obscure.⁸

A misconception around TSS is that it affects menstruating women and children only, which is untrue as it can occur in men even without obvious skin changes. It presents as a febrile illness like in our patient and within few hours can progress to severe hypotension and multiple organ failure.⁸ Our patient had MRSA isolated in culture and TSS due to MRSA strains have been described in a case series in France and Switzerland where 5 out of 30 patients with TSS toxin (TSST) producing MRSA had shock.⁹

Both staphylococcal and streptococcal variants are encountered in the second decade of life with the staphylococcal variant being associated with gastrointestinal symptoms in 90% cases as well as generalised erythroderma.¹⁰ It is more common in women and local invasive disease is not seen, unlike streptococcal TSS. Microbiological diagnosis is important due to variation in the mortality according to the aetiology, staphylococcal (5.0%) compared with streptococcal (50%).¹⁰

Thus, staphylococcal TSS presents with non-specific symptoms and is difficult to diagnose.

Assays detecting both TSST-1 and antibodies against it are commercially available. Patients with poor response to TSS have been found to have antibody titres of <1:5 while healthy population have titres of >1:100.¹¹

The diagnosis is often clinical and antibiotic therapy has to be started empirically due to the high risk of multiorgan failure. The initial presentation is non-specific, with fever, hypotension and rashes which may be seen in a wide variety of diseases. Features like rapid deterioration of vitals, toxicity out of proportion to local findings or unexpected worsening of laboratory parameters should prompt a search for possible causes of TSS.¹¹ The presence of leucocytosis and predominance of immature cells usually indicate severe underlying infections. In some cases, cerebrospinal fluid studies may be warranted to reach the diagnosis.

The diagnostic criteria of TSS as outlined by the Centers for Disease Control and Prevention (CDC), Case Definition 2011¹² and its conformity with our case is given in table 4. To confirm the diagnosis, laboratory criteria, as well as all five clinical criteria and desquamation, has to be present. Assays that identify the TSST-1 by PCR were not available at our centre and thus could not be tested for.

Specific therapy with clindamycin and linezolid is preferred as these agents can neutralise the TSST-1 production, but linezolid has a potential to cause thrombocytopaenia as a cumulative dose related adverse effect hence should be used with caution. Intravenous immunoglobulin and corticosteroids are also reported to be beneficial, but in view of clinical improvement with antibiotics, they were not used in our case.

The last population-based assessment of TSS was done in 1986, but over the past 30 years there have been several significant changes in the causative agents, particularly the rise of community-acquired (CA) MRSA. A study from 2000 to 2006 by DeVries et al conducted in Minneapolis showed that of 7491 admissions, there were 61 cases of TSS. MRSA, however, accounted for only 7% of admissions with an annual incidence of 0.52 per 100 000 population. They attribute this low incidence to the CDC definition which helps identify the more severe cases but leads to underestimation of cases.¹³

A recent hospital-based multicentre study was undertaken in India by Indian Network for Surveillance of Antimicrobial Resistance (INSAR) group¹⁴, which showed that 28% of isolates taken from outpatients grew MRSA in culture.¹⁴ D’Souza et al ¹⁵ studied 412 confirmed cases of MRSA and found that 54% of them were true CA-MRSA possessing the SCCmec IV and SCCmec V genes. These were primarily isolated from skin and soft-tissue infections and demonstrated variable resistance to ciprofloxacin, erythromycin, clindamycin and tetracycline. Resistance to linezolid, however, was not reported. A study by Lin and Peterson¹⁶ reports that patients infected with MRSA suffer a more protracted course of illness, have higher hospital charges and higher rates of mortality than patients infected with methicillin-sensitive S. aureus. Invasive infections with MRSA reportedly account for an estimated 19 000 deaths annually in the USA. Further complicating the public health scenario is the fact that CA-MRSA has a different antibiotic susceptibility profile and produces different toxins as compared with the hospital-acquired MRSA.¹⁵ This makes early institution of effective management difficult until the organism is correctly identified.

Learning points.

• Toxic shock syndrome can affect both menstrual women and non-menstrual adults.

• Thorough clinical examination may reveal crucial findings missed or neglected by patients.

• The diagnosis should be considered in patients of fever, rash and hepatorenal dysfunction who show clinical deterioration despite optimal therapy.

• Early identification with aggressive therapy can improve the outcome in these patients.