Coexistence of atypical Mycoplasma pneumoniae, Hepatitis A with extrapulmonary tuberculosis in one patient presenting as cold agglutinin is rare. We report a case of 29-year-old male presenting with history of low grade fever, yellowish discoloration of eyes and pain in abdomen. On initial routine investigations diagnosed as pancytopenia, cold agglutinin disease, Hepatitis A, and Mycoplasma pneumoniae. Further investigation including bone marrow biopsy revealed granulomas and positron emission tomography-computed tomography showed tiny deep seated lymph node which on further excision confirms tuberculous lymphadenitis with positive acid fast bacillus. The patient responded well to treatment and recovered completely in due course of time.
Keywords: Cold agglutinin, Hepatitis A, Mycoplasma pneumoniae, tuberculosis
Cold agglutinin disease is a hemolytic anemia associated with cold reactive autoantibodies. These antibodies commonly IgM subtype which bind against erythrocyte antigen at cold temperature. Acute form of cold agglutinin disease can be attributed to autoimmune or infectious diseases and lymphoproliferative diseases. Postinfectious cold agglutinins are seen most often Mycoplasma pneumoniae but also with viral pathogens including Epstein–Barr virus, Cytomegalovirus, rubella, Hepatitis C and legionella. Hepatitis A is a liver disease caused by the Hepatitis A virus. Severity of disease and mortality increases in older age groups. Infection usually causes more severe symptoms, with jaundice occurring in more than 70% of cases.
M. pneumoniae is a common cause of community-acquired pneumonia, and the disease usually has a prolonged, gradual onset. The organism responsible for mycoplasmal pneumonia, M. pneumoniae, is a pleomorphic organism that, unlike bacteria, lacks a cell wall, and unlike viruses, does not need a host cell for replication. Although M. pneumoniae is a common cause of pneumonia, only 5–10% of infected patients actually develop pneumonia. Many patients infected with M. pneumoniae remain asymptomatic, but patients who become symptomatic develop a respiratory infection which can be lingering and quite bothersome. The bacterium can also cause a wide array of extrapulmonary manifestations without obvious respiratory disease. Therefore, patients may have a highly variable presentation.
Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis (TB). TB is responsible for up to 43% of peripheral lymphadenopathy in the developing world. Hematological abnormalities associated with extrapulmonary TB include anemia of different types, leukemoid reaction, and rarely pancytopenia. Bone marrow biopsy has been widely used as one of the diagnostic tools when blood counts show a picture of pancytopenia.
There is a considerable increase in positron emission tomography-computed tomography (PET-CT) referrals for patients with fever of unknown origin (FUO). In India, TB is known to be the commonest infection to present as FUO.
This case highlights the significance of clinical, hematological, histological picture, and PET-CT in the final confirmation of TB associated with M. pneumoniae which may otherwise be incomplete with limited investigations.
A 29-year-old male came with fever low grade not associated with chills and rigor, abdominal pain, jaundice for 25 days. He was admitted at a local hospital, reports showed increased erythrocyte sedimentation rate (ESR), increased liver enzymes with hyperbilirubinemia, anemia, urinary tract infection, upper gastrointestinal endoscopy showing gastroenteritis, D1-duodenitis, and antral gastritis.
The patient referred to our hospital for further management. At presentation he had same symptoms with reddish discoloration of urine for one day. General examination revealed icterus, febrile 100 F, PR: 82/min, BP: 110/70 mm Hg and RR: 30/min. Systemic examination was unremarkable. Routine investigation showed pancytopenia hemoglobin:7.60 gms%, total leukocyte count:2800 cells/cumm, platelets:1 Lakh/cumm, RBC indices including MCV:156, MCH:72 markedly increased, peripheral smear showed normocytic normochromic with significant RBCs agglutination, normal differential and morphology, and EDTA sample showed gross agglutination. ESR:98 mm. Direct (anti-Ig G negative and anti C3 D positive) and indirect Coombs test came positive. Cold agglutinin titer was high (1:80). Reticulocyte count was 4.5%. Liver function test, total bilirubin 7.50 mg/dl, indirect 2.30 mg/dl direct 5.20 mg/dl, SGOT 229 U/L, SGPT 156 U/L, total proteins 5.70 gm/dl. Viral serology was nonreactive while anti-HAV IgM (Hepatitis A virus) positive. Radiological examination like chest x-ray and CT chest had done. Chest x-ray appeared normal while CT showed right basal lung consolidation. In view of significant agglutination and visible clumping and pancytopenia, [Figure 1] atypical pneumonia panel including mycoplasma IgM and bone marrow aspiration and trephine biopsy advised and done. Mycoplasma IgM came positive. Diagnosis of cold agglutinin disease complicated by mycoplasma infection made and treated accordingly. Bone marrow aspiration was dry tap while bone marrow biopsy revealed granulomas and acid fast bacillus (AFB) staining was noncontibutory. PET-CT showed right cervical, deep seated single lymph node. Excision of lymph node had done and sent for histopathological examination, which showed caseation necrosis [Figure 4] and histiocytic infiltrate. AFB staining for lymph node biopsy [Figure 5] revealed many acid fast bacilli and reported as tuberculous lymphadenitis. The patient treated with anti-tuberculous drugs and macrolides (Clarithromycin).
Patient fever subsided, total leukocyte count came to normal values, bilirubin reduced to 2.1 gm/dl. Transfusion therapy was not required. The patient improved and was discharged in good health after 7 days. He was thoroughly counseled regarding his health status and precaution measures were discussed (i.e., keeping himself warm).
In review and literature there has been few reported cases of cold agglutinin disease secondary to mycoplasma infection but we believe this to be the first report of its association with M. pneumonia in conjunction with Hepatitis A and extrapulmonary tuberculosis. Though M. pneumonia infections are often asymptomatic, multiple organ systems can be affected. Respiratory tract involvement and extrapulmonary complications in cold agglutinin disease manifest in 3-10% and 25% of the patients, respectively, and autoimmune reactions supposedly play a role in their pathogenesis. Antibody mediated hemolysis is supposedly caused by the formation of cold agglutinins in 10% patients with M. pneumonia infections.,
Cold agglutinins are IgM auto-antibodies which effectively activate the classical complement cascade. In cold hemagglutinin disease, complement is the only protein detected in the red cells in the majority of cases, since IgM dissociates from red cells at higher temperatures. Cold agglutinin is responsible for RBCs agglutination [Figure 2] and increased RBCs indices, as seen in our case. It is the anti-Cd3 component of polyspecific AHG (anti-C3d and anti-IgG) that is responsible for the positive direct Coombs test.
TB is a contagious infection that can present with a variable clinical picture, hence, making the diagnosis difficult. Hematological abnormalities associated with extrapulmonary TB include anemia of different types, leukemoid reaction, and rarely pancytopenia. Bone marrow biopsy [Figure 3]a and [Figure 3]b has been widely used as one of the diagnostic tools when blood counts show a picture of pancytopenia. Though considered a treatable condition, bone marrow tuberculosis has been reportedly associated with fatal outcome., The baseline workup toward the definite diagnosis of TB is usually a noninvasive approach and has significant yield.
Routine imaging studies did not prove very helpful in our case as his chest x-ray did not show any characteristic finding, however CT scan showed basal consolidation which favors mycoplasma infection but not tuberculosis. The tuberculin skin test was negative, but skin tests are unreliable as these are usually negative in patients with extrapulmonary TB.
Extrapulmonary TB can present with variable hematologic abnormalities including anemia, leucopenia, leukocytosis, thrombocytopenia, thrombocytosis and monocytosis, and rarely pancytopenia. In our case, laboratory investigations revealed hematological and biochemical abnormalities that included pancytopenia and raised bilirubin. Several factors are considered to cause pancytopenia in disseminated or extrapulmonary tuberculosis including hypersplenism, histiocytic hyperplasia, maturational arrest, or infiltration of the bone marrow by caseating or noncaseating granulomas causing reversible or irreversible fibrosis.
In the literature, there is no systematic pattern of diagnostic approach and several diagnostic tests including invasive procedures have been used to confirm the diagnosis. In our case, examination of the bone marrow was requested as patient had pancytopenia with significant RBCs agglutination. The findings of bone marrow granulomas give further clue for other chronic inflammation. As there is no palpable lymph node, PET-CT planned which shows subcentimeter deep seated right mid cervical lymph node with difficult access for biopsy, which further confirms the diagnosis.
Co-occurrence of cold agglutinin disease, mycoplasma infection Hepatitis A, and tuberculosis is rare and accumulation of case reports is imperative to enhance our knowledge of this condition. This case is reported for its uncommon presentation and clinical and lab approach for final diagnosis and possible clinical outcome.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]