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Case report Acute paroxysmal cold haemoglobinuria; a case report and literature review

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Paroxysmal cold hemoglobinuria (PCH) is a very rare subtype of autoimmune hemolytic anemia caused by the presence of cold-reacting autoantibodies in the blood and characterized by the sudden presence of hemoglobinuria, typically after exposure to cold temperatures. The acute onset PCH occurs following viral illnesses whilst the chronic form is secondary to hematological malignancies and tertiary syphilis. It is a complement mediated intravascular hemolytic anemia associated with a biphasic antibody against the P antigen on red cells. We describe a three year child who had acute onset PCH following likely viral infection. The diagnosis was confirmed by demonstration of strongly positive Donnath Landsteiner antibodies. She made a gradual recovery with supportive treatment, ten days following the initial detection of haemolysis. Parents were educated about the need to avoid cold exposure to prevent precipitation of further haemolysis and folic acid was commenced to assist the recovery of erythropoiesis.
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Bangladesh Journal of Medical Science Vol. 20 No. 03 July’21
Case report
Acute paroxysmal cold haemoglobinuria; a case report and literature review
Hasitha Gajaweera1, Kavinda Dayasiri2, Nayani Suraweera3, Chandrachapa Gamage4,
Kumudu Weerasekara5
Abstract
Paroxysmal cold hemoglobinuria (PCH) is a very rare subtype of autoimmune hemolytic
anemiacausedbythepresenceofcold-reactingautoantibodiesinthebloodandcharacterizedby
thesuddenpresenceofhemoglobinuria,typicallyafterexposuretocoldtemperatures.Theacute
onsetPCHoccursfollowingviralillnesseswhilstthechronicformissecondarytohematological
malignanciesandtertiarysyphilis.Itisacomplementmediatedintravascularhemolyticanemia
associatedwithabiphasicantibodyagainstthePantigenonredcells.Wedescribeathreeyear
childwhohadacuteonsetPCHfollowinglikelyviralinfection.Thediagnosiswasconrmed
by demonstration of strongly positive Donnath Landsteiner antibodies. She made a gradual
recovery with supportive treatment, ten days following the initial detection of haemolysis.
Parentswereeducatedabouttheneedtoavoidcoldexposuretopreventprecipitationoffurther
haemolysisandfolicacidwascommencedtoassisttherecoveryoferythropoiesis.
Correspondence to: Dr. Kavinda Dayasiri, Lady Ridgeway Children’s hospital, Colombo, Sri Lanka.
E-mail: kavindadayasiri@gmail.com
1. HasithaGajaweera,MBBSMDSeniorRegistrarinPaediatricRespiratoryMedicine
2. KavindaDayasiri,MBBSMDMPhilFRCPCH,SeniorRegistrarinPaediatrics
3. NayaniSuraweera,MBBSMD,SeniorRegistrarinPaediatrics
4. ChandrachapaGamage,MBBSMD,SeniorRegistrarinHematology
5. KumuduWeerasekara,MBBSMDMRCPCH,ConsultantPaediatrician
 LadyRidgewayChildren’shospital,Colombo,SriLanka
Bangladesh Journal of Medical Science Vol. 20 No. 03 July’21. Page : 654-657
DOI: https://doi.org/10.3329/bjms.v20i3.52811
Introduction
Paroxysmal cold hemoglobinuria (PCH) is a
rare subtype of autoimmune hemolytic anemia
characterizedbypresenceof biphasic cold reactive
IgG type autoantibodies against p antigen on red
bloodcells.Theseantibodiesresultincomplement-
mediatedintravascularhemolysisfollowingexposure
tocoldtemperaturesandpatientpresentswithacute
onsetheamoglobinuria.WhilstacutePCHcanoccur
following viral infections and chronic PCH can
presentsecondarilytochronicmedicalillnessessuch
ashaematologicalmalignancies,andtertiarysyphilis.
The cold reactive IgG antibody is also known as
“Donnath Landsteiner” antibody which was rst
described by Julius Donath and Karl Landsteiner in
medical literature. Donnath Landsteiner antibodies
bind red blood cells at colder temperatures and
antibodyboundredbloodcellsundergocomplement
mediated haemolysis while circulating through
warmer temperatures. The characteristic features
of acute PCH include haemolytic anemia and
haemoglobinuria.
Paroxysmal cold heamoglobinuria accounts for less
than 1% of all autoimmune haemolytic anaemias,.
The estimated annual incidence of PCH was 0.4
casesper100,000 population inonestudy.Herein,
the authors describe a child who had paroxysmal
coldhaemaglobinuriafollowingaviralinfection.
Case report
A three year old girl who was previously healthy
andborntonon-consanguineousparentsfromalow
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Acuteparoxysmalcoldhaemoglobinuria;acasereportandliteraturereview
socialbackground, presented withacute onset cola
coloururineforonedayduration.Therehadbeena
precedinghistoryofupperrespiratorytractinfection
2weeksbeforetheonsetofillness.Colacolourwas
moreintenseduringearlymorning.Therehadbeenno
historyofexposuretocoldclimatesortemperatures.
Urineoutputwasnotreduced.Thechilddidnothave
symptomsof anemiaor heartfailure onadmission
totheward.Therewasnorecentmedicationhistory.
Further clinical evaluation did not reveal features of
malignancy, infections or connective tissue disorders.
Examination revealed a pale and icteric child
with adequate physical growth (weight –10 kg,
height – 94 cm). There was no lymphadenopathy,
rashes, arthritis, oral ulcers, exudative tonsillitis or
hepatosplenomegaly.Cardiovascularandrespiratory
systems were clinically normal.  Table 1 shows
sequentialhematologicalindices and bilirubin over
the course of illness.
Table 1 - Variation of hematological indices and
bilirubin over the course of illness
1
week
prior
Day 1 Day 2 Day 3 Day 4 Day 5 Day 7
Hemoglobin
(g/dl) 12.5 9.2 5.1 5.2 5.4 5.6 6
Platelets (x 109)333 390 360 347 348 323 325
TotalBilirubin
(mg/dl) -129 127 172 131 53 34
Indirect
Bilirubin (mg/
dl)
-86 104 146 103 43 26
Full blood count revealed normochromic normocytic
anemia.Bloodpictureshowedpolychromaticcells,
red cell agglutinins and erythrophagocytosis with
evidence of cold autoimmune haemolytic anemia.
Reticulocytecountwas0.8%.Liverfunctions were
withinnormallimits(SGOT–43U/L,SGPT–35).
Serumcreatininewas28µmol/landbloodureawas
7.3mg/dl.DirectCoombstestwaspositivewithC3d
specicity.Epstein-Barrvirus,Cytomegalovirusand
Mycoplasmaserologywerenegative.Urineanalysis
revealed haemoglobinuria and haemosiderinuria
whilsthaematuriawasabsent.DonnathLandsteiner
antibodieswerestronglypositive.
Thechildwasmanagedwithintravenousuids,blood
transfusions and warming with regular monitoring
of hematological indices and serum bilirubin. She
madeagradualrecovery10daysfollowingtheinitial
detection of haemolysis. Parents were educated
about the need to avoid cold exposure to prevent
precipitationoffurtherhaemolysisandfolicacidwas
commencedtoassisttherecoveryoferythropoiesis.
Discussion
The rst report of PCH as a syndrome of passage
of red coloured urine upon exposure to cold was
coinedin1872.PCHweredescribedpredominantly
following secondary and tertiary syphyllis in the
past,.Presently,PCHisknowntofollowanumberof
viralillnesses,suchasparvovirusB19,Epstein-Barr
virus,coxsackievirusA9,mumps,inuenza,chicken
pox, measles, cytomegalovirus, and adenovirus,,.
However,aspecictriggerisnotidentiedinmany
children14,16.PCHhavealsobeenreportedinpatients
withchroniclymphocyticleukemia.
Although acute onset haemolysis and
haemoglobinurisin PCH occurfollowing exposure
tocoldtemperatures,occasionally ahistoryofcold
exposure may not be present. Children are more
susceptibleforacute PCH andcanpresent with an
isolated,shortlasting,hemolyticepisodefollowinga
viralinfection.However,recurrentepisodesofPCH
in children have been reported127. Haemolysis is
usuallyrapidlyprogressiveandcanbelifethreatening
leading to severe anaemia. Reticulocyte count is
oftenlow for the degree ofanaemia suggesting an
inadequate bone marrow response due to marrow
suppressionfromviralinfection.
The clinical features of PCH include passage of
red or brown coloured urine (heamoglobinuria),
abdominalpain,headache,fever,malaise,feverwith
chills,andvomiting.Accumulationofbilepigments
canrarelyleadtoacutekidneyinjury.IgMmediated
cold autoimmune haemolytic anaemia is the main
dierentialdiagnosis.
TheantibodyinPCHiscold-reactiveIgG.Although
IgG antibodies do not cause red cell agglutination as
seenwithIgM,IgGboundredcellsreadilyundergo
complement mediated haemolysis. This leads to
intravascularhemolysisin warm temperatures. The
rate of haemolysis at dierent temperatures is
variableindierentpatients.
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HasithaGajaweera,KavindaDayasiri, et al.
The gold standard for diagnosis of PCH is
demonstration of Donnath-Landsteiner antibodies.
DonnathLandsteinerantibodieswererstdescribed
in1904.Theseantibodiesusuallyappear1weekafter
theonsetofhaemolysisandcanbedemonstratedup
to three months.
Treatmentismainlysupportive.Adequatehydration,
pain relief and avoidance of cold form a key part
of management. Red cell transfusions are indicated
forpatientswithsevereanaemiaandacutewarming
helps in mitigating severe haemolysis. It is also
important to monitor blood counts, reticulocyte
countandifindicated,renalfunctionsuntilcomplete
recovery. Immunosuppressive therapy may be
eectiveinseverecases.Inmostchildrenwithcute
PCH,haemolysisisself-limitingandsupportivecare
and monitoring are all that is required. However,
untreated children can develop acute kidney
injuryandcomplicationsfollowingsevereanemia.
Funding–Notapplicable
Conict of Interest – None declared
Acknowledgement – None
Written consent has been obtained from index
patient’sparents
Ethical clearance–Notapplicable
Authors’ contribution – HG, KD, NS, CG, KW
clinically managed the patient, HG, KD, NS
performed literature survey, HG, KD, NS, CG
preparedthemanuscript,KWsupervisedpreparation
of the manuscript, All authors approved the nal
versionofmanuscript.
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Acuteparoxysmalcoldhaemoglobinuria;acasereportandliteraturereview
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Article
Rationale Dengue fever is capable of inciting the formation of transient polyclonal antibodies directed at red blood cell antigens, resulting in complement-mediated hemolysis, leading to intravascular hemolysis and hemoglobinuria. Patient’s concern A 12-year-old male patient who recovered from dengue fever a week ago had red blood cell agglutination, spherocytes, and engulfment of red blood cells (erythrophagocytosis) by monocytes and neutrophils on routine hematological peripheral blood smear. The unexpected blood smear results prompted the lab physicians to investigate autoimmune hemolytic anemia, which revealed a monospecific positive direct antiglobulin test for complement (C3d, C3b) and the presence of Donath-Landsteiner antibody. Diagnosis Paroxysmal cold hemoglobinuria (PCH), secondary to dengue fever. Interventions Oxygen supplements, antibiotics, intravenous immunoglobulins, steroid therapy, and packed cell transfusions were administered. Outcomes The patient’s condition was improved following the therapy. Lessons Post-dengue PCH is a rare complication that requires a thorough peripheral smear examination for erythrophagocytosis, as advanced hematology analyzers fail to detect such findings.
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Paroxysmal cold hemoglobinuria is caused by a biphasic IgG autoantibody that triggers complement-mediated intravascular hemolysis. Paroxysmal cold hemoglobinuria has not previously been reported to occur in association with pregnancy. We report a case of an 18 year old female who presented in early pregnancy with acute hemolytic anemia and a positive Donath-Landsteiner antibody test. She was diagnosed with paroxysmal cold hemoglobinuria and treated supportively. Her hemolysis resolved within 6 weeks. Because maternal IgG autoantibodies can cross the placenta, the patient was monitored closely throughout her pregnancy for recurrence. The outcome of the pregnancy was successful, with no evidence of neonatal anemia or hemolysis. This patient had a classic presentation of paroxysmal cold hemoglobinuria with rapid onset of hemolytic anemia that resolved spontaneously. To our knowledge, this is the first report of paroxysmal cold hemoglobinuria presenting during pregnancy.
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PCH is a rare autoimmune hemolytic anemia (AIHA) but is one of the most common causes of AIAH in children. For the diagnosis, it is important to perform the appropriate methods of serological investigation and show the typical biphasic reaction. This is a case report of a child who presented with features of haemolysis and was diagnosed with PCH of this way.
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The clinical outcome, response to treatment, and occurrence of acute complications were retrospectively investigated in 308 primary autoimmune hemolytic anemia (AIHA) cases and correlated with serological characteristics and severity of anemia at onset. Patients had been followed up for a median of 33 months (range 12-372); 60% were warm AIHA, 27% cold hemagglutinin disease, 8% mixed, and 5% atypical (mostly direct antiglobulin test negative). The latter 2 categories more frequently showed a severe onset (hemoglobin [Hb] levels ≤6 g/dL) along with reticulocytopenia. The majority of warm AIHA patients received first-line steroid therapy only, whereas patients with mixed and atypical forms were more frequently treated with 2 or more therapy lines, including splenectomy, immunosuppressants, and rituximab. The cumulative incidence of relapse was increased in more severe cases (hazard ratio 3.08; 95% confidence interval, 1.44-6.57 for Hb ≤6 g/dL; P < .001). Thrombotic events were associated with Hb levels ≤6 g/dL at onset, intravascular hemolysis, and previous splenectomy. Predictors of a fatal outcome were severe infections, particularly in splenectomized cases, acute renal failure, Evans syndrome, and multitreatment (4 or more lines). The identification of severe and potentially fatal AIHA in a largely heterogeneous disease requires particular experienced attention by clinicians.
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PCH is one of the most common causes of acute AIHA in young children, although it affects patients of all ages. In children it is commonly seen following a viral illness or after immunization. Donath Landsteiner test is the diagnostic test. This is a case report of a child who presented with features of haemolysis and was diagnosed as PCH.
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Autoimmune hemolytic anemia (AIHA) is a heterogeneous disease usually classified as warm, cold [cold agglutinin disease (CAD)] or mixed, according to the thermal range of the autoantibody. Diagnosis is based on the direct antiglobulin test (DAT), typically positive with anti-IgG antisera in warm AIHA and anti-C3d in CAD. Diagnostic pitfalls are due to IgA autoantibodies, warm IgM, low-affinity IgG, or IgG below the threshold of sensitivity, and about 5% of AIHA remains DAT negative. The treatment of AIHA is still not evidence-based. Corticostreroids are the first-line therapy for warm AIHA. For refractory/relapsed cases the choice is between splenectomy (effective in ∼70% cases but with a presumed cure rate of 20%) and rituximab (effective in ~70-80% of cases) which is becoming the preferred second-line treatment, and thereafter any of the immunesuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Rituximab is now recommended as first-line treatment for CAD. Additional therapies are intravenous immunoglobulins, danazol, and plasma-exchange, alemtuzumab and high-dose cyclophosphamide as last options.
Article
Donath-Landsteiner (DL) antibodies are immunoglobulins formed in response to a viral, bacterial, or spirochete infection and are capable of inducing Paroxysmal Cold Hemoglobinuria (PCH), an autoimmune hemolytic anemia. In the past, PCH was most commonly associated with syphilitic infections; however, now it is more frequently identified as a sequela in pediatric patients with upper respiratory infections. The authors present a case of a 5-year-old female who presented with hemolytic anemia and was subsequently diagnosed with PCH.
Article
. During the last 4 years, we have studied a total of 531 adults and 68 children with clinically and serologically well-defined forms of immune hemolytic anemias. Among these, Donath-Landsteiner (DL) hemolysis was the underlying disease in 22 of the 68 children (32.4%), but was not observed in adults. All children with DL hemolysis suffered from acute infections presumably of viral origin. In none of the cases was the DL hemolysis suspected clinically. Boys were more often affected than girls. The hemolytic episodes were severe, but resolved within few weeks. Serologically, all patients had a strongly positive direct antiglobulin test (DAT) using anti-C3d reagents, but a weak (n = 6) or negative (n = 16) IgG-DAT. DL hemolysins were always weak and transient, detectable with enzyme-treated red blood cells (RBC) in all, with untreated RBC in 12 of 22 sera. To explore the reason why these weak antibodies can cause extensive hemolysis in vivo, we compared the action of DL antibodies and of cold agglutinins (anti-I) on RBC by several reincubations at 4 and at 37°C. The data obtained from this experiment demonstrate a stronger aggravation of hemolysis by DL than by anti-I antibodies, presumably due to low-affinity interaction between the cells and DL antibodies.