A New Cause for Confusion or Concern – A Case Series

Dominic Rodriguez*, Suresh Chelliah

Department of Internal Medicine and Paediatrics, Kauvery hospital, Trichy, India

*Correspondence: Email: [email protected]

Background

The year 2020 was unique experience many physicians will enjoy talking about to students and juniors in the years to come. Present scenario differs from the previous year in the way patients present to us having symptoms and signs of familiar but, confounded by presence of acute or past COVID-19 infection. The authors present three cases where the initial confusion was overcome by logical deduction aided by a competent laboratory.

Clinical Presentation

Case 1

A 11-year-old girl presented on the sixth day of high-grade fever with watery loose stools, poor intake and tiredness. She was febrile, 104°F; heart rate, 112 bpm; RR, 28 bpm; SPO2, 99%. Toxic with pharyngeal ulcers, right posterior cervical lymphadenopathy. RS, CVS normal, no hepatosplenomegaly. Baseline tests including blood culture was obtained and COVID-19 antibody was also requested. Screening CT thorax done, though she had no respiratory symptoms CT showed small homogenous opacities in two areas

Important results

Hb
TC
P 83, L 13, M 2
Platelets
INR
aPTT ratio
Procalcitonin
CRP
D DIMER
LDH
Ferritin
COVID-19 RT-PCR
COVID-19 antibody		 11.8 gm/dl
2900 cells/cu.mm

81,000
1.25
1.36
0.52 (< 0.5 normal)
62.6 MG/L
3575.14 ng/ml
505
> 1200
Negative
>20 units

With the clinical features and investigations, a diagnosis of MIS-C (multisystem inflammatory syndrome in children) was considered [1]. However, blood culture showed a growth of Salmonella typhi.

She improved with ceftriaxone and steroids that were started before culture reports were available.

Case 2

A 11-year-old girl was brought with complaints of high-grade fever for six days, multiple episodes of vomiting for two days and altered sensorium. She had hepatomegaly and was febrile. Blood investigations revealed leukopenia, thrombocytopenia and high CRP. COVID IgG was positive. Though these criteria are in favour of MISC CAT-1, growth of S. typhi in blood culture was against it. Serum ferritin 8190 ng/ml. Hemophagocytosis was considered a possibility and steroid was started one day after giving antibiotics. She improved well.

Case 3

A 14-year-old girl was admitted with vomiting and altered sensorium with thrombocytopenia. She was referred as a case of ITP after receiving IV steroids

Investigation ruled out an autoimmune disorder. COVID IgG was positive. Serum ferritin was 14388 ng/ml and D-dimer was 4420 ng/ml. Blood culture showed S. typhi similar to previous case. There was good improvement clinically and haematologically with antibiotics and steroids.

Discussion

In these three cases, typhoid who had evidence of past history of SARS–CoV-2 infection with evidence of a multi system inflammatory disorder fulfilling the criteria for MIS-C are presented. Two of these children with HLH are discussed.

Clinical presentation, positive COVID status and other investigations were suggestive of MIS-C. But in all children, there was an evidence of other infection, the absence of which is a prerequisite for diagnosis of MIS-C.

WHO case definition of MIS-C.

All six criteria must be met:

  1. Age 0 to 19 years.
  2. Fever for ≥ 3 days.
  3. Clinical signs of multisystem involvement (at least two of the following):
    1. Rash, bilateral non purulent conjunctivitis, or mucocutaneous inflammation signs (oral, hands, or feet).
    2. Hypotension or shock.
    3. Cardiac dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin/BNP).
    4. Evidence of coagulopathy (prolonged PT or PTT; elevated D-dimer).
    5. Acute gastrointestinal symptoms (diarrhoea, vomiting, or abdominal pain).
  4. Elevated markers of inflammation (e.g., ESR, CRP, or procalcitonin).
  5. No other obvious microbial cause of inflammation, including bacterial sepsis and staphylococcal/streptococcal toxic shock syndromes.
  6. Evidence of SARS-CoV-2 infection. Any of the following:
    1. Positive SARS–CoV-2 RT–PCR.
    2. Positive serology.
    3. Positive antigen test.
    4. Contact with an individual with COVID-19.

Hemophagocytic lymphohistiocytosis is a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes that commonly appears in infancy. Fever, hepatosplenomegaly, pancytopenia, lymphadenopathy and rash compromise the initial presentation

Hemophagocytosis, typically seen in children under 18 years can be treated successfully, if diagnosed early. Evidence of hemophagocytosis in bone marrow is pathognomonic hepatosplenomegaly, seen in other HLH syndromes due direct infiltration of macrophages and lymphocytes has not yet been reported in COVID-19 patients. Some children with MIS-C have developed macrophage activated phenotypes. Increased levels of ferritin, D-dimer, ALT, triglycerides and LDH are seen in most cases. Treatment consists of anti-inflammatory drugs such as corticosteroids, cyclosporin, anti-IL1 agents and etoposide [2]. Plasma exchange is often needed.

Diagnostic criteria for HLH

The presence of at least five of the eight of the following features:

  1. Fever ≥ 38.5°C.
  2. Splenomegaly.
  3. Peripheral blood cytopenia.
  4. Hypertriglyceridemia and/or hypofibrinogenemia.
  5. Hemophagocytosis in bone marrow, spleen, lymph node, or liver.
  6. Low or absent NK cell activity.
  7. Ferritin > 500 ng/mL
  8. Elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms.

There is considerable overlap between MIS-C and HLH, both considered an immune response to infection.

Association of typhoid and HLH is known but coexistence of COVID-19 is not widely recorded in the literature. HLH may be complication of dengue and typhoid. Association of dengue and typhoid with a past COVID-19 infection is unusual and we could not find an association after a fairly detailed search. The association could still be coincidental. Whether the inflammatory response to the infection was amplified due to post COVID-19 status needs larger prospective studies to determine the causal nature of the association.

The confusion

  1. COVID-19 infections – past or present
    1. School’s reopening
    2. Primary infection being asymptomatic.
  2. Elevation of D-dimer, CRP, ferritin, LDH, all indicating severe inflammation as seen in MIS-C (rarely encountered in other severe bacterial infections).
  3. No specific localizing signs for other infections.

Cause for concern

  1. If bacterial infection is not tested for, ruled out, or picked up by cultures, steroid or immunomodulatory treatment alone can be disastrous. However, a careful consideration is to be given to start steroids under antibiotic cover. Inflammatory syndromes occur post infection and concern about worsening of the infection may be secondary, if the situation demands [3].
  2. In spite of appropriate testing before treatment for MIS-C, cultures could be false negative.

What is the way out?

Approach to a young patient with fever – COVID times

  1. Age < 20 years
  2. Fever > 3 days

Clinical assessment

Check for multisystem involvement

  1. Rash, conjunctivitis, mucositis, swollen hands, feet.
  2. Tongue, pharyngitis.
  3. Lymphadenopathy.
  4. Cardiac: hypotension, shock. ECHO for coronary artery aneurysm.
  5. GI: diarrhoea, vomiting, abdominal pain.
  6. Blood: coagulopathy, D-dimer elevation.

Check

  1. CRP, ferritin, LDH.
  2. Send blood culture, procalcitonin.
  3. RT–PCR for COVID and COVID antibody (we seldom think of doing these tests but now it is relevant to do so).

If COVID antibody is negative most probably we are dealing with a non – COVID syndrome.

Reported mimics are toxic shock syndrome, Staphylococcal and Streptococcal infections.

In addition, we have seen a number of children with scrub typhus and looking for an eschar is essential too.

In our patients it was due to S. typhi.

Empirical antibiotic therapy pending blood culture results is justified in these circumstances.

References

  1. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet. 2020;395(10237):1607–1608.
  2. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in US children and adolescents. N Engl J Med. 2020;383(4):334-346.
  3. Henderson LA, Canna SW, Friedman KG, et al. American college of rheumatology clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS‐C) associated with SARS–CoV‐2 and hyperinflammation in COVID‐19: version 2. Arthritis Rheumatol. 2020; doi.org/10.1002/art.41616.

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