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A. Khorochkov
some studies show that autoantibodies for AIBD among the healthy population are
generally low, suggesting that these diseases may develop over time [4].
However, less common subsets of AIBD are often overlooked; anti-p200 pemphigoid is a rarer form with IgG antibodies directed against laminin gamma-1, a
200kDa protein within the basement membrane lamina lucida [5]. BP is recognized
by autoantibodies against BP180 and BP 230 [6]. While these and many other variants of pemphigoid may afict patients presenting with cutaneous symptoms, the
standard workup for BP remains limited, which in the case chosen here for discussion can lead to initial treatment failure as a result of misdiagnosis [1]. Anti-p200
pemphigoid shares the BP200 target with epidermolysis bullosa acquisita (EBA),
which is considered another close differential but additionally targets anti-laminin
332 [7]. IIF microscopy with salt-split human skin in BIOCHIP can distinguish
between oor-binding and roof-binding immune reactants, as well as offer a form of
uid blister testing standardization [7–9].
Immunouorescence is an essential tool for the diagnosis of autoimmune blistering disease; direct immunouorescence (DIF) is the current standard; however, the
higher sensitivity for salt-split skin methodology in indirect immunouorescence
(IIF) is necessary in suspected BP refractory to treatment and may reect an initial
inaccuracy in diagnosis [1, 10]. Here we see a case where the initial misdiagnosis of
BP due to incomplete workup was rectied by further investigation with IIF conrming anti-p200 pemphigoid [1]. The current gold standard of BP diagnosis is DIF
visualization of membrane-bound autoantibodies in the skin or mucosa, together
with clinical features [11]. However, DIF without further workup with IIF is not
capable of differentiating between entities of pemphigoid disease as demonstrated
here [7].
Clinical Case Presentation
A male patient aged 60years sought medical assistance for a generalized, blistering
rash. It was erythematous with papules and herpetiform vesicles on the trunk, axillae, palms, upper extremities, buttocks, inner thighs, toes, and ulcers on the
tongue palate.
Punch biopsies for routine histopathology and direct immunouorescence (DIF)
showed a subepidermal blister with neutrophils, a linear band of C3, and IgG at the
dermal-epidermal junction suspicious for unusual bullous pemphigoid (BP).
However, further histopathology and DIF were consistent with BP. The patient
started oral dapsone without improvement despite taking 50mg prednisone daily
for over a month with persistent aring.
He was then started on dupilumab; however, the presentation was concerning for
an AIBD other than BP, warranting further workup. Repeat biopsies showed a subepidermal blister with a mixed dermal inltrate and a smooth band of IgG and C3
with an n-serration pattern consistent with BP.
9 Using Indirect Immunouorescence in Unveiling Unknown Pemphoids and…
61
Nevertheless, enzyme-linked immunosorbent assay (ELISA) for BP antibodies
was not supportive. ELISA was negative for antinuclear antibodies, as was ELISA
for antibodies which ruled out paraneoplastic pemphigus, pemphigus vulgaris,
pemphigus foliaceus, and epidermolysis bullosa acquisita. Indirect immunouorescence (IIF) on rat bladder epithelium and monkey esophagus was negative, thus
eliminating pemphigus vulgaris and paraneoplastic pemphigus. However, IIF on
salt-split skin showed strong binding of IgG4 and IgG antibodies to the dermal
oor, consistent with EBA, anti-laminin 332 mucous membrane pemphigoid
(MMP), anti-p105 pemphigoid, and anti-p200 pemphigoid. There is a lack of commercially available tests for anti-p200 (laminin gamma-1), anti-laminin 332, or
anti-p105, which could ease this diagnostic process. By exclusion, the patient was
diagnosed with anti-p200 pemphigoid, the most common pemphigoid that shows
serum antibodies binding to the dermal oor of human salt-split skin IIF, thus revising the initial diagnosis of BP.Furthermore, in contrast to BP, anti-p200 pemphigoid
exhibits prominent mucosal, palmoplantar, and cephalic involvement. This was
seen in the patient with an earlier onset age than BP.Anti-p105 pemphigoid is less
likely due to the clinical presentation, as it clinically resembles toxic epidermal
necrolysis or pemphigus vulgaris. Dupilumab was discontinued in favor of an
increased dose of prednisone to 100mg daily, two infusions of rituximab separated
by 2 weeks, and initiation of dapsone 100 mg daily. He experienced promising
improvement and continued on prednisone 60mg daily 1month after the last dose
of rituximab.
Differential Diagnosis
1. Anti-p200 Pemphigoid– Is a rare subepidermal condition belonging to autoim-
mune bullous disease. It is diagnosed by indirect immunouorescence through
the identication of a 200-kd protein. Clinical characteristics include urticarial
plaques and tense blisters with erosions that mimic bullous pemphigoid and epidermolysis bullosa acquisita.
2. Bullous Pemphigoid—Is a disorder of autoimmune blistering where bullae are
uid-lled, larger than 1cm, and pruritic. It more commonly affects patients
above age 70. Autoantibodies target hemidesmosomes in the epidermal-dermal
junction, mainly at BP180 and BP 230, which distinguishes it from even rarer
forms of pemphigoid. Direct immunouorescence shows a linear band. Topical
steroids are rst-line management.
3. Epidermolysis Bullosa Acquisita– Is a chronic blistering autoimmune disease
affecting the cutaneous and mucosal regions. Autoantibodies target type VII collagen in the dermal-epidermal junction. It presents as blisters, erosions, fragile
skin, and nail loss. Supportive care and maintenance of the skin barrier are mainstays for management.
62
A. Khorochkov
What WasMisdiagnosed inThis Case andWhy?
The patient was misdiagnosed with bullous pemphigoid conrmed by direct immunouorescence which was later corrected to the diagnosis of anti-p200 pemphigoid
after an unsuccessful course of treatment and further workup with indirect
immunouorescence.
Discussion
AIBD encompasses various entities of BP, including anti-p200 pemphigoid [1].
However, the initial workup with DIF is not sufcient to distinguish these subsets
and can lead to a treatment-resistant course due to initial misdiagnosis [1]. The
patient discussed in the highlighted case had DIF and histopathology results concerning for a rare BP [1]. No further workup was done at this time, and treatment
was started on oral dapsone without improvement despite receiving prednisone for
1month [1]. Additional trials with dupilumab and prednisone were ineffective [1].
Eventually, enzyme-linked immunosorbent assay (ELISA) for BP antibodies were
inconsistent with the clinical presentation; IIF showed strong binding of IgG and
IgG4 BMZ antibodies to the dermal oor, and it was eventually determined to be
anti-p200 pemphigoid despite a lack of commercially available screening tools for
anti-p105 also present in this subset [1]. The patient continued to have ares until
management was revised to a higher dose of prednisone, two infusions of rituximab,
and dapsone daily [1].
The diagnosis of AIBD starts with the clinical characteristics and a patient
encounter detailing the disease [12]. Next, histopathology may provide information
differentiating between pemphigus and pemphigoid disease [12]. Currently, DIF
microscopy is the gold standard for detecting tissue-bound antibodies, with a specicity of 98% and a sensitivity of 91%; however, there is a limit to the antigens that
can be targeted [12]. Characteristic linear binding of IgG and C3 at the dermalepidermal junction is typical of pemphigoid disease, while further pattern differentiation determines the subset [12]. Nevertheless, serological detection of circulating
antibodies is minimally invasive and does not require a biopsy [12]. It relies on IIF
used in conjunction with DIF for a complete clinical picture [12]. Recombinant
antigens can also be used in ELISA, which has added value in monitoring disease
activity [12].
Further complicating the presentation of AIBD, not all patients with BP form
blisters [14]. Unusual AIBD presentations are still largely uncategorized: BP may be
mimicked by unique forms of bullous eczema and only identied by biopsies showing eosinophilic spongiosis [13]. The diagnosis of both bullous and non- bullous
pemphigoid variants necessitates a full workup including both DIF and IIF; ELISA
is valuable for monitoring the activity of the disease [14]. Specically, clinicians
should be aware that IIF can differentiate between BP and epidermolysis bullosa
acquisita, as in the discussed case, they performed several tests, and a diagnosis was
9 Using Indirect Immunouorescence in Unveiling Unknown Pemphoids and…
63
determined by process of elimination [1, 15]. The use of rat bladder epithelium as a
substrate in IIF has been shown to be a more sensitive substrate for the diagnosis of
BP as compared to monkey esophagus, although it is comparatively lacking in specicity; nevertheless, it is easier and faster than the salt-split skin technique which is
a benet in the timely distinction of BP from EBA [16]. However, the predictive
values of IIF have not yet been standardized [17]. Alternative studies suggest that
monkey esophagus may be a more reliable substrate if pemphigus vulgaris or pemphigus foliaceus are suspected [17]. Conversely, normal human skin in some literature is preferred to monkey esophagus because it is at least as sensitive for serological
BP diagnosis, and BP180 is genetically different in humans and monkeys [18].
Full diagnosis workup for AIBD includes a clinical examination, lesional skin
biopsy for histology, DIF of a perilesional sample, and IIF of serum on monkey
esophagus [18]. With the standardization of this process, fewer misdiagnoses are
likely in suspected AIBD; IIF is a necessary component to distinguish BP from
other rarer conditions, including anti-p200 pemphigoid [1]. Commercially available
tests for anti-p200 (laminin gamma-1), anti-p105, and anti-laminin 332 would be
assets in the diagnostic clarity of AIBD [1]. The awareness of rarer AIBD types,
including anti-p200 pemphigoid and epidermolysis bullosa acquisita, availability of
these commercial tests, and standard practice of IIF in the diagnostic workup can
minimize delays in nding appropriate treatment strategies [1]. The patient in the
assessed case arrived at the diagnosis of anti-p200 pemphigoid; however, there is
continued suspicion for other yet undiscovered forms of pemphigoid; nevertheless,
the original misdiagnosis of BP was excluded [1]. Clinicians can benet from
increased awareness of AIBD types and the use of IIF in the diagnostic strategy [1].
Conclusion
Subsets within AIBD often have similar presentations within this group, and BP is
primarily the most diagnosed. However, BP may appear similarly clinically and
with partial workup, including DIF microscopy. It is only on further investigation
with IIF that a distinction is evident between BP, anti-p200, and epidermolysis bullosa acquisita. Increased clinical awareness for rare AIBD presentations, the standardization of IIF, and the development of targeted commercial tests will reduce the
likelihood of misdiagnosis.
References
1. Hopkins CR, Ren V, Grover R, Cockerell C, Hsu S. When bullous pemphigoid is not bullous pemphigoid: the importance of going beyond direct immunouorescence. Cureus.
2022;14(2):e22201. Published 2022 Feb 14. https://doi.org/10.7759/cureus.22201.
2. Burruss CP, Jones JM, Burruss JB.Semaglutide-associated bullous pemphigoid. JAAD Case
Rep. 2021;15:107–9. Published 2021 Aug 5. https://doi.org/10.1016/j.jdcr.2021.07.027.
64
3. Vornicescu C, Șenilă SC, Cosgarea R, Candrea E, Pop AD, Ungureanu L.Pemphigoid nodularis- rare presentation of bullous pemphigoid: a case report and literature review. Exp Ther
Med. 2019;17(2):1132–8. https://doi.org/10.3892/etm.2018.7057.
4. Prüßmann W, Prüßmann J, Koga H, etal. Prevalence of pemphigus and pemphigoid autoantibodies in the general population. Orphanet J Rare Dis. 2015;10:63. Published 2015 May 15.
https://doi.org/10.1186/s13023- 015- 0278- x.
5. García-Díez, etal. Usefulness of a simple Immunohistochemical staining technique to differentiate anti-p200 pemphigoid from other autoimmune blistering diseases: a report of 2 cases.
Actas dermo-siliogracas. 2017;108(1):e1–5. https://doi.org/10.1016/j.ad.2015.10.019.
6. Gornowicz-Porowska J, Seraszek-Jaros A, Bowszyc-Dmochowska M, et al. Accuracy of
molecular diagnostics in pemphigus and bullous pemphigoid: comparison of commercial and
modied mosaic indirect immunouorescence tests as well as enzyme-linked immunosorbent
assays. Postepy Dermatol Alergol. 2017;34(1):21–7. https://doi.org/10.5114/ada.2017.65617.
7. Rai R, Anand JB, Shanmugasekar C, etal. Anti-P 200 pemphigoid- the most common oor
binding subepidermal autoimmune bullous disease in a tertiary care center in South India. Indian
J Dermatol Venereol Leprol. 2021;87(6):787–91. https://doi.org/10.25259/IJDVL_79_20.
8. Arunprasath P, Rai R, Venkataswamy C. Comparative analysis of BIOCHIP mosaic-based
indirect immunouorescence with direct immunouorescence in diagnosis of autoimmune
bullous diseases: a cross-sectional study. Indian. Dermatol Online J. 2020;11(6):915–9.
Published 2020 Nov 8. https://doi.org/10.4103/idoj.IDOJ_156_20.
9. Sernicola A, Russo I, Saponeri A, Alaibac M.Biochip detection of BP180 autoantibodies in
blister uid for the serodiagnosis of bullous pemphigoid: a pilot study. Medicine (Baltimore).
2019;98(7):e14514. https://doi.org/10.1097/MD.0000000000014514.
10. Arbache ST, Nogueira TG, Delgado L, Miyamoto D, Aoki V.Immunouorescence testing in
the diagnosis of autoimmune blistering diseases: overview of 10-year experience. An Bras
Dermatol. 2014;89(6):885–9. https://doi.org/10.1590/abd1806- 4841.20143221.
11. van Beek N, Rentzsch K, Probst C, etal. Serological diagnosis of autoimmune bullous skin
diseases: prospective comparison of the BIOCHIP mosaic-based indirect immunouorescence technique with the conventional multi-step single test strategy. Orphanet J Rare Dis.
2012;7:49. Published 2012 Aug 9. https://doi.org/10.1186/1750- 1172- 7- 49.
12. Saschenbrecker S, Karl I, Komorowski L, et al. Serological Diagnosis of Autoimmune
Bullous Skin Diseases. Front Immunol. 2019;10:1974. Published 2019 Aug 20. https://doi.
org/10.3389/mmu.2019.01974.
13. Atteh G, Cole EF, Perricone AJ, Feldman RJ. Bullous eczema presenting as bullous
pemphigoid- like eruption: a case series. JAAD Case Rep. 2021;10:34–7. Published 2021 Feb
7. https://doi.org/10.1016/j.jdcr.2021.01.032.
14. Meijer JM, Diercks GFH, de Lang EWG, Pas HH, Jonkman MF. Assessment of diagnostic strategy for early recognition of bullous and nonbullous variants of pemphigoid. JAMA
Dermatol. 2019;155(2):158–65. https://doi.org/10.1001/jamadermatol.2018.4390.
15. Yang B, Wang C, Chen S, et al. Accuracy of indirect immunouorescence on sodium
chloride-split skin in the differential diagnosis of bullous pemphigoid and epidermolysis bullosa acquisita. Indian J Dermatol Venereol Leprol. 2011;77(6):677–82. https://doi.
org/10.4103/0378- 6323.86479.
16. Delmonte S, Cozzani E, Drosera M, Parodi A, Rebora A. Rat bladder epithelium: a sensitive substrate for indirect immunouorescence of bullous pemphigoid. Acta Derm Venereol.
2000;80(3):175–8. https://doi.org/10.1080/000155500750042916.
17. Kridin K, Bergman R. The usefulness of indirect immunouorescence in pemphigus
and the natural history of patients with initial false-positive results: a retrospective cohort
study. Front Med (Lausanne). 2018;5:266. Published 2018 Oct 17. https://doi.org/10.3389/
fmed.2018.00266.
18. Emtenani S, Yuan H, Lin C, etal. Normal human skin is superior to monkey oesophagus substrate for detection of circulating BP180-NC16A-specic IgG antibodies in bullous pemphigoid. Br J Dermatol. 2019;180(5):1099–106. https://doi.org/10.1111/bjd.17313.
A. Khorochkov
Part II
Cardiology
Chapter 10
Infective Endocarditis Misdiagnosed
asCommunity-Acquired Pneumonia
RaviVintha andPrakrutNishamanishSethi
Learning Objectives
By the end of this presentation, the clinician will be able to:
1. Discuss the important facts about community-acquired pneumonia.
2. Differentiate between community-acquired pneumonia and aortic valve
endocarditis.
3. Compare and contrast between aortic valve endocarditis and noninfective
endocarditis.
4. Differentiate clinically between aortic valve endocarditis and prosthetic valve
thrombosis.
5. Analyze the consequences of a misdiagnosis or delay in reaching a correct diagnosis for the individual patient prognosis, for the transmission of bacterial endocarditis, and for public health.
Introduction
The diagnosis and treatment options for community-acquired pneumonia have been
widely addressed by healthcare experts for decades, but unfortunately, the diagnostic errors still occur often in clinical practice. Community-acquired pneumonia,
according to many authors, is one of the most misdiagnosed illnesses, with diagnostic mistakes ranging from 7% to 67% [1, 2].
R. Vintha (*) · P. N. Sethi
St. Martinus University Faculty of Medicine, Willemstad, Curacao
e-mail: ravi.vintha@martinus.edu; prakrut.sethi@martinus.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_10
67
68
R. Vintha and P. N. Sethi
On the one hand, various illnesses have been identied as “masks of pneumonia.” Community-acquired pneumonia, on the other hand, can resemble a variety of
conditions, including neurological problems and acute abdomen. Any illness with a
high incidence of respiratory symptoms is extremely likely to be diagnosed as
community- acquired pneumonia in clinical practice [3–6].
Making a diagnosis of community-acquired pneumonia or ruling it out may
appear simple due to clear guidelines and diagnostic criteria. However, when
patients are in a severe state, especially if they have a fever and/or respiratory failure, ruling out pneumonia can be challenging [6, 7].
Differential Diagnosis
1. Noninfective endocarditis/nonbacterial thrombotic endocarditis (NBTE) –
Nonbacterial thrombotic endocarditis is a rare, noninfective form of endocarditis
due to sterile platelet thrombus formation on the heart valves (usually mitral and
aortic valves). There can be many causes for the disease like malignancy, hypercoagulable states, underlying trauma, previous rheumatic fever, and autoimmune conditions like systemic lupus erythematosus, rheumatoid arthritis, and antiphospholipid
syndrome. Chronic infections like tuberculosis, pneumonia, and osteomyelitis can
also lead to nonbacterial thrombotic endocarditis. The clinical features compared to
infective endocarditis, vegetations are easily dislodged, and embolization is common, leading to hemorrhages under the nails, skin, and retina. Most affected individuals are asymptomatic until embolization occurs. In infective endocarditis, the
body’s response is inammation, whereas nonbacterial thrombotic endocarditis
does not cause an inammatory response. Biopsy is the denitive diagnosis:
• Sterile vegetations on either surface of the valve are composed of immune
complexes, mononuclear cells, and thrombi interwoven with brin strands.
• Not always feasible, therefore diagnosis is mostly made based on the clinical
ndings, no response to antibiotic treatment, negative blood cultures, and
echocardiography ndings. Treatment: anticoagulation with heparin [8–10].
2. Prosthetic valve thrombosis (PVT)– It usually affects mechanical valves and is
rare if anticoagulation is adequate. It is caused mainly due to insufcient anticoagulation therapy after valve replacement. The clinical features shows signs of
acute heart failure:
• Left heart failure: difculty breathing and cough
• Right heart failure: jugular venous distention and edema
• Other signs and symptoms include deterioration of general condition, cardiac
arrhythmias, and cerebral emboli, i.e., stroke.
10 Infective Endocarditis Misdiagnosed asCommunity-Acquired Pneumonia
69
• Prosthetic valve thrombosis is diagnosed by transesophageal echocardiogra-
phy while it is treated by
• Anticoagulation and brinolysis
• Surgical valve replacement [11]
Clinical Case Presentation
A 48-year-old man was admitted to intensive care in a critical condition with the
primary diagnosis of severe community-acquired pneumonia of both lower lobes of
both lungs. The patient complains of shortness of breath at rest, exhaustion, chest
pain that worsens with deep breathing, and a fever of up to 40°C.On admission:
patient is awake but disoriented, with pale skin, marked dyspnea at rest, respiratory
rate of 32, oxygen saturation of 92 percent, temperature of 40°C, heart rate of 90
per minute, and blood pressure of 90/60 mm hg. The lungs were examined and
found to have weak vesicular breathing in both lower lobes. Heart auscultation
reveals a modest systolic murmur at the apex, and leukocytosis on the complete
blood count.
Past Medical History: He has been sick for the past 11days. Fever and exhaustion were the rst signs. He began taking an antibiotic (can’t recall the name of the
prescription) on the rst day of his illness, but it had no clinical effect. The fever
remained, and chest pain had happened 2 days before admission.
Concomitant diseases:
• Spontaneous coronary artery dissection (SCAD): class III
• Myocardial infarction (2016)
• Persistent atrial brillation (AF)
• CHADS2-VASC score: 0 (congestive heart failure, hypertension, age≥75years,
diabetes mellitus, prior stroke, vascular disease, age 65–74 years, sex cate-
gory) [12]
• Congestive Heart Failure: CHF,II A with preserved ejection fraction (EF) (58%)
• He took aspirin 100mg and bisoprolol 5mg regularly for these ailments. In the
intensive care unit, the patient was given intravenous ceftriaxone 2,0g+levo-
oxacin 500mg, as well as oxygen. The patient did not demonstrate any clinical
improvement after 48hours of treatment. The patient’s vital signs were tempera-
ture up to 40°C, chest pain, leukocytosis, C-reactive protein 239mg/l, T2 levels
96ng/ml. Atrial brillation paroxysm on electrocardiography (ECG). Troponin
testing was negative.
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R. Vintha and P. N. Sethi
Discussion
The computed tomography scan revealed no inltration in the lung tissue, but it did
reveal minor hydrothorax and hydropericardium. Hence, bacterial endocarditis was
suspected in the patient. As a result, he had echocardiography, which revealed only
aortic valve brosis and mitral and tricuspid valve regurgitation, and ejection fraction was retained (58%). As these tests conrmed that the earlier diagnosis and
treatment administered for community-acquired pneumonia were incorrect, the
course of treatment was changed to an antibacterial treatment (vancomycin
1,5g+meropenem 3g daily), and an antiarrhythmic drug was introduced (amiodarone 600mg daily). The patient showed mild clinical improvement but deteriorated
again on the sixth day of treatment. Another echocardiography was conducted, and
this time there was evidence of possible aortic valve vegetation. The patient was
sent to the department of cardiac surgery for further evaluation (transesophageal
echocardiography) and treatment. Unfortunately, he deteriorated and died 24h after
the move. Aortic valve endocarditis was established by autopsy. The absence of
clinical symptoms of pneumonia as well as inltrative alterations on computed
tomography scan helped to rule out community-acquired pneumonia in this patient.
High levels of indicators of systemic inammation and disease progression, on the
other hand, were suggestive of a septic process, and paroxysms of atrial brillation,
as well as episodes of left ventricular failure, helped to suspect and diagnose bacterial endocarditis. However, the pathological process continued for much too long
before the diagnosis was veried, resulting in multiple organ insufciency.
Conclusion
In conclusion, we wanted to use this clinical case to emphasize the signicance of
differential diagnosis in severe patients who are rst suspected of pneumonia but
later lack adequate clinical proof. In order to achieve an accurate diagnosis as
quickly as possible, it’s vital to keep in mind a variety of potentially fatal diseases
that look like pneumonia, especially the ones discussed earlier. Despite advancements in diagnostic and microbiological methods, infectious endocarditis is still
associated with severe morbidity and mortality. Measures that have been proven to
improve patient outcomes include early diagnosis, early participation of a focused
infective endocarditis team, and rapid surgical surgery when necessary [7].
References
1. Singh H, Giardina TD, Meyer AN, Forjuoh SN, Reis MD, Thomas EJ.Types and origins of
diagnostic errors in primary care settings. JAMA Intern Med. 2013;173(6):418–25.